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Passos PRC, Vieira AA, de Melo RPM, Pinheiro Filho RF, Sampaio LG, dos Santos HVG, Sampaio LR, Goes JVC, Magalhães SMM, Pinheiro RF. Clustering Based on Innate Immunity Reveals Differential Dysregulation Based on Disease Severity in Myelodysplastic Neoplasms. Hematol Oncol 2025; 43:e70104. [PMID: 40397075 PMCID: PMC12094220 DOI: 10.1002/hon.70104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/17/2025] [Accepted: 05/09/2025] [Indexed: 05/22/2025]
Abstract
Myelodysplastic neoplasms (MDS) are clonal hematologic disorders characterized by ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia (AML). Despite growing recognition of the role of innate immunity in MDS pathogenesis, the precise mechanisms remain unclear. In this study, we analyzed bone marrow CD34+ expression data from 183 MDS patients to investigate the impact of the Toll-like receptor (TLR) pathway on disease progression. Six key innate immunity genes (IRAK1, IRAK2, IRAK4, MYD88, TRAF6, and NFKB1) were used to define two distinct immune clusters: a hyperactive immune cluster (HIC) and a moderate immune cluster (MIC). The HIC was enriched in 155 immune-related pathways and showed higher infiltration of activated natural killer cells and M1 macrophages, while the MIC exhibited increased infiltration of naïve B cells and mast cells. Differential expression analysis identified 35 genes that distinguished the clusters. Validation in an independent cohort of 82 patients revealed that reduced expression of these genes correlated with markers of advanced disease, including lower hemoglobin levels, lower neutrophil counts, altered cytogenetics, and higher bone marrow blast percentages. These findings underscore the critical role of immune dysregulation in MDS progression and highlight novel therapeutic opportunities within the innate immunity pathway for tailored interventions.
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Affiliation(s)
- Pedro Robson Costa Passos
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
| | - Andréa Alcântara Vieira
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
- Postgraduate Program in Medical SciencesFederal University of CearáFortalezaBrazil
| | - Renata Pinheiro Martins de Melo
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
| | - Ronald Feitosa Pinheiro Filho
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
| | - Leonardo Guimarães Sampaio
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
| | | | - Letícia Rodrigues Sampaio
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
- Postgraduate Program in Medical SciencesFederal University of CearáFortalezaBrazil
| | - João Victor Caetano Goes
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
- Postgraduate Program in PathologyFederal University of CearáFortalezaBrazil
| | - Sílvia Maria Meira Magalhães
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
- Postgraduate Program in Medical SciencesFederal University of CearáFortalezaBrazil
- Postgraduate Program in PathologyFederal University of CearáFortalezaBrazil
- Department of Clinical MedicineFederal University of CearáFortalezaBrazil
| | - Ronald Feitosa Pinheiro
- Laboratory of Cancer CytogeneticsFederal University of CearáFortalezaBrazil
- Research Center for Drug Development (NPDM)FortalezaBrazil
- Postgraduate Program in Medical SciencesFederal University of CearáFortalezaBrazil
- Postgraduate Program in PathologyFederal University of CearáFortalezaBrazil
- Department of Clinical MedicineFederal University of CearáFortalezaBrazil
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Jarczak J, Thetchinamoorthy K, Wierzbicka D, Bujko K, Ratajczak MZ, Kucia M. Expression of innate immunity genes in human hematopoietic stem/progenitor cells - single cell RNA-seq analysis. Front Immunol 2025; 16:1515856. [PMID: 40264766 PMCID: PMC12011761 DOI: 10.3389/fimmu.2025.1515856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 03/19/2025] [Indexed: 04/24/2025] Open
Abstract
Background The complement system expressed intracellularly and known as complosome has been indicated as a trigger in the regulation of lymphocyte functioning. The expression of its genes was confirmed also in several types of human bone marrow-derived stem cells: mononuclear cells (MNCs), very small embryonic-like stem cells (VSELs), hematopoietic stem/progenitor cells (HSPCs), endothelial progenitors (EPCs) and mesenchymal stem cells (MSCs). In our previous studies, we demonstrated the expression of complosome proteins including C3, C5, C3aR, and cathepsin L in purified HSPCs. However, there is still a lack of results showing the expression of complosome system elements and other immunity-related proteins in human HSPCs at the level of single cell resolution. Methods We employed scRNA-seq to investigate comprehensively the expression of genes connected with immunity, in two populations of human HSPCs: CD34+Lin-CD45+ and CD133+Lin-CD45+, with the division to subpopulations. We focused on genes coding complosome elements, selected cytokines, and genes related to antigen presentation as well as related to immune regulation. Results We observed the differences in the expression of several genes e.g. C3AR1 and C5AR1 between two populations of HSPCs: CD34+LinCD45+ and CD133+Lin-CD45+ resulting from their heterogeneous nature. However, in both kinds of HSPCs, we observed similar cell subpopulations expressing genes (e.g. NLRP3 and IL-1β) at the same level, which suggests the presence of cells performing similar functions connected with the activation of inflammatory processes contributing to the body's defense against infections. Discussion To our best knowledge, it is the first time that expression of complosome elements was studied in HSPCs at the single cell resolution with the use of single cell sequencing. Thus, our data sheds new light on complosome as a novel regulator of hematopoiesis that involves intracrine activation of the C5a-C5aR-Nlrp3 inflammasome axis.
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Affiliation(s)
- Justyna Jarczak
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Diana Wierzbicka
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Kamila Bujko
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Mariusz Z. Ratajczak
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
| | - Magdalena Kucia
- Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
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An Z, Fan QW, Wang L, Yoda H, Barata MJ, Jimenez-Morales D, Phillips JJ, Swaney DL, Stevenson E, Lee E, Krogan N, Weiss WA. EGFR and EGFRvIII coopt host defense pathways promoting progression in glioblastoma. Neuro Oncol 2025; 27:383-397. [PMID: 39248287 PMCID: PMC11812036 DOI: 10.1093/neuonc/noae182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Indexed: 09/10/2024] Open
Abstract
BACKGROUND Co-amplification of the epidermal growth factor receptor (EGFR) and EGFRvIII, a tumor-specific truncation mutant of EGFR, represent hallmark genetic lesions in glioblastoma. METHODS We used phospho-proteomics, RNA-sequencing, TCGA data, glioblastoma cell culture, and mouse models to study the signal transduction mediated by EGFR and EGFRvIII. RESULTS We report that EGFR and EGFRvIII stimulate the innate immune defense receptor Toll-like Receptor 2 (TLR2); and that knockout of TLR2 dramatically improved survival in orthotopic glioblastoma xenografts. EGFR and EGFRvIII activated TLR2 in a ligand-independent manner, promoting tumor growth and immune evasion. We show that EGFR and EGFRvIII cooperate to activate the Rho-associated protein kinase ROCK2, which modulated malignant progression both by activating TLR2 and WNT signaling, and through remodeling the tumor microenvironment. CONCLUSIONS Together, our findings show that EGFR and EGFRvIII cooperate to drive tumor progression through ROCK2 and downstream WNT-β-catenin/TLR2 signaling pathways.
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Affiliation(s)
- Zhenyi An
- Department of Neurology, University of California, San Francisco, California, USA
| | - Qi-Wen Fan
- Department of Neurology, University of California, San Francisco, California, USA
| | - Linyu Wang
- Department of Neurology, University of California, San Francisco, California, USA
| | - Hiroyuki Yoda
- Department of Neurology, University of California, San Francisco, California, USA
| | - Megumi J Barata
- Department of Neurology, University of California, San Francisco, California, USA
| | - David Jimenez-Morales
- J. David Gladstone Institutes, San Francisco, California, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, California, USA
| | - Joanna J Phillips
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
- Department of Neurological Surgery, University of California, San Francisco, California, USA
| | - Danielle L Swaney
- J. David Gladstone Institutes, San Francisco, California, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, California, USA
| | - Erica Stevenson
- J. David Gladstone Institutes, San Francisco, California, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, California, USA
| | - Ethan Lee
- Department of Cell & Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
| | - Nevan Krogan
- J. David Gladstone Institutes, San Francisco, California, USA
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA
- Quantitative Biosciences Institute (QBI), University of California, San Francisco, California, USA
| | - William A Weiss
- Brain Tumor Research Center, University of California, San Francisco, California, USA
- Department of Pediatrics, University of California, San Francisco, California, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
- Department of Neurological Surgery, University of California, San Francisco, California, USA
- Department of Neurology, University of California, San Francisco, California, USA
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Feng Y, Chen C, Shao A, Wu L, Hu H, Zhang T. Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer. Acta Pharm Sin B 2024; 14:5091-5105. [PMID: 39807338 PMCID: PMC11725142 DOI: 10.1016/j.apsb.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/20/2024] [Accepted: 07/26/2024] [Indexed: 01/16/2025] Open
Abstract
Interleukin-1 receptor-related kinase (IRAK4) is a widely expressed serine/threonine kinase involved in the regulation of innate immunity. IRAK4 plays a pivotal role as a key kinase within the downstream signaling pathway cascades of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs). The signaling pathways orchestrated by IRAK4 are integral to inflammatory responses, and its overexpression is implicated in the pathogenesis of inflammatory diseases, autoimmune disorders, and cancer. Consequently, targeting IRAK4-mediated signaling pathways has emerged as a promising therapeutic strategy. Small molecule inhibitors and degraders designed to modulate IRAK4 have shown efficacy in mitigating related diseases. In this paper, we will provide a detailed description of the structure and function of IRAK4, the role of IRAK4 in related diseases, as well as the currently reported small molecule inhibitors and degraders of IRAK4. It is expected to provide new directions for enriching the clinical treatment of inflammation and related diseases.
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Affiliation(s)
- Yifan Feng
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Chengjuan Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Anqi Shao
- Department of Dermatology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Lei Wu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Haiyu Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Tiantai Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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Stubbins RJ, Cherniawsky H, Karsan A. Cellular and immunotherapies for myelodysplastic syndromes. Semin Hematol 2024; 61:397-408. [PMID: 39426936 DOI: 10.1053/j.seminhematol.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 09/17/2024] [Indexed: 10/21/2024]
Abstract
In this review article, we outline the current landscape of immune and cell therapy-based approaches for patients with myelodysplastic syndromes (MDS). Given the well characterized graft-versus-leukemia (GVL) effect observed with allogeneic hematopoietic cell transplantation, and the known immune escape mechanisms observed in MDS cells, significant interest exists in developing immune-based approaches to treat MDS. These attempts have included antibody-based drugs that block immune escape molecules, such as inhibitors of the PD-1/PD-L1 and TIM-3/galectin-9 axes that mediate interactions between MDS cells and T-lymphocytes, as well as antibodies that block the CD47/SIRPα interaction, which mediates macrophage phagocytosis. Unfortunately, these approaches have been largely unsuccessful. There is significant potential for T-cell engaging therapies and chimeric antigen receptor T (CAR-T) cells, but there are also several limitations to these approaches that are unique to MDS. However, many of these limitations may be overcome by the next generation of cellular therapies, including those with engineered T-cell receptors or natural killer (NK)-cell based platforms. Regardless of the approach, all these immune cells are subject to the complex bone marrow microenvironment in MDS, which harbours a variable and heterogeneous mix of pro-inflammatory cytokines and immunosuppressive elements. Understanding this interaction will be paramount to ensuring the success of immune and cellular therapies in MDS.
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Affiliation(s)
- Ryan J Stubbins
- Leukemia/BMT Program of BC, BC Cancer, Vancouver V5Z 1M9, BC, Canada; Division of Hematology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada.
| | - Hannah Cherniawsky
- Leukemia/BMT Program of BC, BC Cancer, Vancouver V5Z 1M9, BC, Canada; Division of Hematology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
| | - Aly Karsan
- Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 1L3, Canada.
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Kannan S, Vedia RA, Molldrem JJ. The immunobiology of myelodysplastic neoplasms: a mini-review. Front Immunol 2024; 15:1419807. [PMID: 39355256 PMCID: PMC11443505 DOI: 10.3389/fimmu.2024.1419807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/27/2024] [Indexed: 10/03/2024] Open
Abstract
This mini review summarizes the immunobiology of myelodysplastic syndromes, specifically focusing on the interactions between immune cells, cytokines, and dysplastic cells within the tumor microenvironment in the bone marrow. We elucidate in detail how immune dysregulation and evasion influence the initiation and progression of myelodysplastic syndromes, as well as resistance to therapy and progression to AML. In addition, we highlight a range of therapeutic strategies, including the most recent breakthroughs and experimental therapies for treating MDS. Finally, we address the existing knowledge gaps in the understanding of the immunobiology of MDS and propose future research directions, promising advancements toward enhancing clinical outcomes and survival for patients with MDS.
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Affiliation(s)
- Shruthi Kannan
- Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Rolando A Vedia
- Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Jeffrey J Molldrem
- Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Evolution of Cancer, Leukemia, and Immunity Post Stem cEll transplant (ECLIPSE), Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX, United States
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Ye L, Tian C, Li Y, Pan H, Hu J, Shu L, Pan X. Hematopoietic aging: Cellular, molecular, and related mechanisms. Chin Med J (Engl) 2024; 137:1303-1312. [PMID: 37898877 PMCID: PMC11191024 DOI: 10.1097/cm9.0000000000002871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Indexed: 10/30/2023] Open
Abstract
ABSTRACT Aging is accompanied by significant inhibition of hematopoietic and immune system function and disruption of bone marrow structure. Aging-related alterations in the inflammatory response, immunity, and stem cell niches are at the root of hematopoietic aging. Understanding the molecular mechanisms underlying hematopoietic and bone marrow aging can aid the clinical treatment of aging-related diseases. In particular, it is unknown how the niche reprograms hematopoietic stem cells (HSCs) in an age-dependent manner to maintain normal hematopoiesis in elderly individuals. Recently, specific inhibitors and blood exchange methods have been shown to reshape the hematopoietic niche and reverse hematopoietic aging. Here, we present the latest scientific discoveries related to hematopoietic aging and hematopoietic system rejuvenation, discuss the relationships between hematopoietic niche aging and HSC aging, and describe related studies on stem cell-mediated regulation of hematopoietic aging, aiming to provide new ideas for further study.
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Affiliation(s)
- Li Ye
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Chuan Tian
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
| | - Ye Li
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Hang Pan
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Jinxiu Hu
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
| | - Liping Shu
- Department of Immunology of School of Basic Medicine of Guizhou Medical University, National and Local Joint Engineering Laboratory of Cell Engineering Biomedical Technology, Key Laboratory of Regenerative Medicine of Guizhou Province, State Key Laboratory of Efficacy and Utilization of Medicinal Plants Co-constructed by Province and Ministry, Key Laboratory of Translational Research of Adult Stem Cell of Chinese Academy of Medical Sciences, Guiyang, Guizhou 550025, China
| | - Xinghua Pan
- The Stem Cells and Immune Cells Biomedical Techniques Integrated Engineering Laboratory of State and Regions, Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming Key Laboratory of Stem Cell and Regenerative Medicine, Basic Medical Laboratory, 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan 650032, China
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Tsilingiris D, Vallianou NG, Spyrou N, Kounatidis D, Christodoulatos GS, Karampela I, Dalamaga M. Obesity and Leukemia: Biological Mechanisms, Perspectives, and Challenges. Curr Obes Rep 2024; 13:1-34. [PMID: 38159164 PMCID: PMC10933194 DOI: 10.1007/s13679-023-00542-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/06/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE OF REVIEW To examine the epidemiological data on obesity and leukemia; evaluate the effect of obesity on leukemia outcomes in childhood acute lymphoblastic leukemia (ALL) survivors; assess the potential mechanisms through which obesity may increase the risk of leukemia; and provide the effects of obesity management on leukemia. Preventive (diet, physical exercise, obesity pharmacotherapy, bariatric surgery) measures, repurposing drugs, candidate therapeutic agents targeting oncogenic pathways of obesity and insulin resistance in leukemia as well as challenges of the COVID-19 pandemic are also discussed. RECENT FINDINGS Obesity has been implicated in the development of 13 cancers, such as breast, endometrial, colon, renal, esophageal cancers, and multiple myeloma. Leukemia is estimated to account for approximately 2.5% and 3.1% of all new cancer incidence and mortality, respectively, while it represents the most frequent cancer in children younger than 5 years. Current evidence indicates that obesity may have an impact on the risk of leukemia. Increased birthweight may be associated with the development of childhood leukemia. Obesity is also associated with worse outcomes and increased mortality in leukemic patients. However, there are several limitations and challenges in meta-analyses and epidemiological studies. In addition, weight gain may occur in a substantial number of childhood ALL survivors while the majority of studies have documented an increased risk of relapse and mortality among patients with childhood ALL and obesity. The main pathophysiological pathways linking obesity to leukemia include bone marrow adipose tissue; hormones such as insulin and the insulin-like growth factor system as well as sex hormones; pro-inflammatory cytokines, such as IL-6 and TNF-α; adipocytokines, such as adiponectin, leptin, resistin, and visfatin; dyslipidemia and lipid signaling; chronic low-grade inflammation and oxidative stress; and other emerging mechanisms. Obesity represents a risk factor for leukemia, being among the only known risk factors that could be prevented or modified through weight loss, healthy diet, and physical exercise. Pharmacological interventions, repurposing drugs used for cardiometabolic comorbidities, and bariatric surgery may be recommended for leukemia and obesity-related cancer prevention.
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Affiliation(s)
- Dimitrios Tsilingiris
- First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, 68100, Alexandroupolis, Greece
| | - Natalia G Vallianou
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | - Nikolaos Spyrou
- Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, 1190 One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Dimitris Kounatidis
- Department of Internal Medicine, Evangelismos General Hospital, 45-47 Ipsilantou str, 10676, Athens, Greece
| | | | - Irene Karampela
- 2nd Department of Critical Care, Medical School, University of Athens, Attikon General University Hospital, 1 Rimini Str, 12462, Athens, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias str, 11527, Athens, Greece.
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Khalilian P, Eskandari N, Sharifi MJ, Soltani M, Nematollahi P. Toll-Like Receptor 4, 2, and Interleukin 1 Receptor Associated Kinase4: Possible Diagnostic Biomarkers in Myelodysplastic Syndrome Patients. Adv Biomed Res 2024; 13:17. [PMID: 38525404 PMCID: PMC10958736 DOI: 10.4103/abr.abr_67_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/02/2023] [Accepted: 05/10/2023] [Indexed: 03/26/2024] Open
Abstract
Background Myelodysplastic syndrome (MDS) is a clonal hematologic disorder that requires the integration of morphologic, cytogenetic, hematologic, and clinical findings for a successful diagnosis. Trying to find ancillary tests such as biomarkers improve the diagnosis process. Several studies showed that a disordered immune system is associated with MDS. The chronic activated innate immune system, particularly the Toll-like receptors (TLRs) pathway could be involved in the induction of the inflammation. Materials and Methods In the present study, we investigated the expression of TLR2, TLR4, and IRAK4 in bone marrow (BM) of MDS patients, the leukemia group, and the healthy group. For this purpose, we assessed the expression of TLR2, TLR4, and IRAK4 by real time-PCR. Results In line with new findings, we demonstrated that the expression of TLR2, TLR4, and IRAK4 significantly increased in MDS BM compared with the healthy group. Moreover, IRAK4 expression raised significantly in MDS patients compared with other studied hematologic neoplasms. Also, the expression levels of TLR2 and TLR4 significantly increased in MDS in comparison to some studied non-MDS malignancies (P ˂ 0.05). Receiver operating characteristics (ROC) analysis and area under the curve (AUC) suggested that the expression of TLR2, TLR4, and IRAK4 (AUC = 0.702, AUC = 0.75, and AUC = 0.682, respectively) had acceptable diagnostic values to identify MDS from the other understudied leukemias. Conclusion Overall, the expression of TLR2, TLR4, and IRAK4 could be potential biomarkers for discriminating MDS from some hematologic disorders.
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Affiliation(s)
- Parvin Khalilian
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahid Eskandari
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Applied Physiology Research Center, Isfahan Cardiovascular Research Institute, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Jafar Sharifi
- Department of Laboratory Sciences, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Soltani
- Department of Immunology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Pardis Nematollahi
- Department of Pathology, School of Medicine, Cancer Prevention Research Center, Seyyed Al-Shohada Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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10
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Zhao XC, Ju B, Xiu NN, Sun XY, Meng FJ. When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms. Front Immunol 2024; 15:1339971. [PMID: 38426096 PMCID: PMC10902444 DOI: 10.3389/fimmu.2024.1339971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/24/2024] [Indexed: 03/02/2024] Open
Abstract
Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%-15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.
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Affiliation(s)
- Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao, Shandong, China
| | - Fan-Jun Meng
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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11
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Putnam CM, Kondeti L, Kesler MBA, Varney ME. Modulating the immune system as a therapeutic target for myelodysplastic syndromes and acute myeloid leukemia. Biochem Cell Biol 2023; 101:481-495. [PMID: 37566901 DOI: 10.1139/bcb-2022-0374] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2023] Open
Abstract
Modulating the immune system to treat diseases, including myeloid malignancies, has resulted in the development of a multitude of novel therapeutics in recent years. Myelodysplastic syndromes or neoplasms (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that arise from defects in hematopoietic stem and progenitor cells (HSPCs). Dysregulated immune responses, especially in innate immune and inflammatory pathways, are highly associated with the acquisition of HSPC defects in MDS and AML pathogenesis. In addition to utilizing the immune system in immunotherapeutic interventions such as chimeric antigen receptor T cell therapy, vaccines, and immune checkpoint inhibitors, mitigating dysregulation of innate immune and inflammatory responses in MDS and AML remains a priority in slowing the initiation and progression of these myeloid malignancies. This review provides a comprehensive summary of the current progress of diverse strategies to utilize or modulate the immune system in the treatment of MDS and AML.
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Affiliation(s)
- Caroline M Putnam
- Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, USA
| | - Lahari Kondeti
- Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, USA
| | - Meredith B A Kesler
- Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, USA
| | - Melinda E Varney
- Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV, USA
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12
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Guo C, Gao YY, Li ZL. Predicting leukemic transformation in myelodysplastic syndrome using a transcriptomic signature. Front Genet 2023; 14:1235315. [PMID: 37953918 PMCID: PMC10634373 DOI: 10.3389/fgene.2023.1235315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 10/10/2023] [Indexed: 11/14/2023] Open
Abstract
Background: For prediction on leukemic transformation of MDS patients, emerging model based on transcriptomic datasets, exhibited superior predictive power to traditional prognostic systems. While these models were lack of external validation by independent cohorts, and the cell origin (CD34+ sorted cells) limited their feasibility in clinical practice. Methods: Transformation associated co-expressed gene cluster was derived based on GSE58831 ('WGCNA' package, R software). Accordingly, the least absolute shrinkage and selection operator algorithm was implemented to establish a scoring system (i.e., MDS15 score), using training set (GSE58831 originated from CD34+ cells) and testing set (GSE15061 originated from unsorted cells). Results: A total of 68 gene co-expression modules were derived, and the 'brown' module was recognized to be transformation-specific (R2 = 0.23, p = 0.005, enriched in transcription regulating pathways). After 50,000-times LASSO iteration, MDS15 score was established, including the 15-gene expression signature. The predictive power (AUC and Harrison's C index) of MDS15 model was superior to that of IPSS/WPSS in both training set (AUC/C index 0.749/0.777) and testing set (AUC/C index 0.933/0.86). Conclusion: By gene co-expression analysis, the crucial gene module was discovered, and a novel prognostic system (MDS15) was established, which was validated not only by another independent cohort, but by a different cell origin.
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Affiliation(s)
| | | | - Zhen-Ling Li
- Department of Hematology, China-Japan Friendship Hospital, Beijing, China
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13
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Vallelonga V, Gandolfi F, Ficara F, Della Porta MG, Ghisletti S. Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes. Biomedicines 2023; 11:2613. [PMID: 37892987 PMCID: PMC10603842 DOI: 10.3390/biomedicines11102613] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/15/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Inflammation impacts human hematopoiesis across physiologic and pathologic conditions, as signals derived from the bone marrow microenvironment, such as pro-inflammatory cytokines and chemokines, have been shown to alter hematopoietic stem cell (HSCs) homeostasis. Dysregulated inflammation can skew HSC fate-related decisions, leading to aberrant hematopoiesis and potentially contributing to the pathogenesis of hematological disorders such as myelodysplastic syndromes (MDS). Recently, emerging studies have used single-cell sequencing and muti-omic approaches to investigate HSC cellular heterogeneity and gene expression in normal hematopoiesis as well as in myeloid malignancies. This review summarizes recent reports mechanistically dissecting the role of inflammatory signaling and innate immune response activation due to MDS progression. Furthermore, we highlight the growing importance of using multi-omic techniques, such as single-cell profiling and deconvolution methods, to unravel MDSs' heterogeneity. These approaches have provided valuable insights into the patterns of clonal evolution that drive MDS progression and have elucidated the impact of inflammation on the composition of the bone marrow immune microenvironment in MDS.
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Affiliation(s)
- Veronica Vallelonga
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, 20139 Milan, Italy
| | - Francesco Gandolfi
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, 20139 Milan, Italy
| | - Francesca Ficara
- Milan Unit, CNR-IRGB, 20090 Milan, Italy
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
| | - Matteo Giovanni Della Porta
- IRCCS Humanitas Research Hospital, 20089 Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
| | - Serena Ghisletti
- Department of Experimental Oncology, European Institute of Oncology (IEO) IRCCS, 20139 Milan, Italy
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14
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Schneider M, Rolfs C, Trumpp M, Winter S, Fischer L, Richter M, Menger V, Nenoff K, Grieb N, Metzeler KH, Kubasch AS, Sockel K, Thiede C, Wu J, Woo J, Brüderle A, Hofbauer LC, Lützner J, Roth A, Cross M, Platzbecker U. Activation of distinct inflammatory pathways in subgroups of LR-MDS. Leukemia 2023; 37:1709-1718. [PMID: 37420006 PMCID: PMC10400420 DOI: 10.1038/s41375-023-01949-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/17/2023] [Accepted: 06/19/2023] [Indexed: 07/09/2023]
Abstract
Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1β and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1-mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B, were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies.
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Affiliation(s)
- Marie Schneider
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Clara Rolfs
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Matthias Trumpp
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Susann Winter
- Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Luise Fischer
- Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Mandy Richter
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Victoria Menger
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Kolja Nenoff
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Nora Grieb
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Klaus H Metzeler
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Anne Sophie Kubasch
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Katja Sockel
- Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Christian Thiede
- Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Jincheng Wu
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Janghee Woo
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | | | - Lorenz C Hofbauer
- UniversityCenter for Healthy Aging & Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Jörg Lützner
- Department of Orthopedic Surgery, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Andreas Roth
- Department of Orthopedic Surgery, University Medical Center Leipzig, Leipzig, Germany
| | - Michael Cross
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany
| | - Uwe Platzbecker
- Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Medical Center Leipzig, Leipzig, Germany.
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15
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Vegivinti CTR, Keesari PR, Veeraballi S, Martins Maia CMP, Mehta AK, Lavu RR, Thakur RK, Tella SH, Patel R, Kakumani VK, Pulakurthi YS, Aluri S, Aggarwal RK, Ramachandra N, Zhao R, Sahu S, Shastri A, Verma A. Role of innate immunological/inflammatory pathways in myelodysplastic syndromes and AML: a narrative review. Exp Hematol Oncol 2023; 12:60. [PMID: 37422676 DOI: 10.1186/s40164-023-00422-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 06/22/2023] [Indexed: 07/10/2023] Open
Abstract
Dysregulation of the innate immune system and inflammatory-related pathways has been implicated in hematopoietic defects in the bone marrow microenvironment and associated with aging, clonal hematopoiesis, myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). As the innate immune system and its pathway regulators have been implicated in the pathogenesis of MDS/AML, novel approaches targeting these pathways have shown promising results. Variability in expression of Toll like receptors (TLRs), abnormal levels of MyD88 and subsequent activation of NF-κβ, dysregulated IL1-receptor associated kinases (IRAK), alterations in TGF-β and SMAD signaling, high levels of S100A8/A9 have all been implicated in pathogenesis of MDS/AML. In this review we not only discuss the interplay of various innate immune pathways in MDS pathogenesis but also focus on potential therapeutic targets from recent clinical trials including the use of monoclonal antibodies and small molecule inhibitors against these pathways.
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Affiliation(s)
- Charan Thej Reddy Vegivinti
- Department of Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY, 10461, US
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | | | | | | | - Ansh Krishnachandra Mehta
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
- Department of Hematology and Oncology, Jacobi Medical Center/ Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | - Rohit Reddy Lavu
- Department of Oncology, Yashoda hospitals, Hyderabad, 500036, India
| | - Rahul Kumar Thakur
- Department of Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY, 10461, US
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | - Sri Harsha Tella
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, US
| | - Riya Patel
- Department of Hematology and Oncology, University of Buffalo - Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, US
| | | | | | - Srinivas Aluri
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | | | - Nandini Ramachandra
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | - Rongbao Zhao
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | - Srabani Sahu
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | - Aditi Shastri
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US
- Department of Oncology, Blood Cancer Institute, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, 10461, US
| | - Amit Verma
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, US.
- Department of Oncology, Blood Cancer Institute, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, 10461, US.
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16
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Trova S, Lin F, Lomada S, Fenton M, Chauhan B, Adams A, Puri A, Di Maio A, Wieland T, Sewell D, Dick K, Wiseman D, Wilks DP, Goodall M, Drayson MT, Khanim FL, Bunce CM. Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation. PLoS One 2023; 18:e0288162. [PMID: 37418424 PMCID: PMC10328239 DOI: 10.1371/journal.pone.0288162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 06/15/2023] [Indexed: 07/09/2023] Open
Abstract
A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1β from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating that in vivo exposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3 differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1β secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-κB and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1β in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases.
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Affiliation(s)
- Sandro Trova
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Fei Lin
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Santosh Lomada
- Institute of Experimental and Clinical Pharmacology and Toxicology, Heidelberg University, Mannheim, Germany
| | - Matthew Fenton
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Bhavini Chauhan
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Alexandra Adams
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Avani Puri
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Alessandro Di Maio
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Thomas Wieland
- Institute of Experimental and Clinical Pharmacology and Toxicology, Heidelberg University, Mannheim, Germany
| | - Daniel Sewell
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Kirstin Dick
- School of Biosciences, University of Birmingham, Birmingham, United Kingdom
| | - Daniel Wiseman
- Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Deepti P. Wilks
- Cancer Research UK Manchester Institute, Manchester Cancer Research Centre Biobank, The University of Manchester, Manchester, United Kingdom
| | - Margaret Goodall
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Mark T. Drayson
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Farhat L. Khanim
- Clinical Sciences, University of Birmingham, Birmingham, United Kingdom
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17
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Sun XY, Yang XD, Xu J, Xiu NN, Ju B, Zhao XC. Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome: A case report and review of literature. World J Clin Cases 2023; 11:4713-4722. [PMID: 37469724 PMCID: PMC10353497 DOI: 10.12998/wjcc.v11.i19.4713] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/22/2023] [Accepted: 05/31/2023] [Indexed: 06/30/2023] Open
Abstract
BACKGROUND Myelodysplastic syndrome (MDS) is caused by malignant proliferation and ineffective hematopoiesis. Oncogenic somatic mutations and increased apoptosis, necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells. An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage. Bone marrow cellularity and myeloblasts usually increase with disease progression. However, aplastic crisis occasionally occurs in advanced MDS.
CASE SUMMARY A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1 (MDS-EB-1) based on an increase in the percentages of myeloblasts and cluster of differentiation (CD)34+ hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples. The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years. In the treatment process, the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia. During the aplastic crisis, the bone marrow was infiltrated with sparsely distributed atypical lymphocytes. Surprisingly, the leukemic cells disappeared. Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3, CD5, CD8, CD16, CD56 and CD57, suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer (NK)/NKT cells that suppressed both normal and leukemic hematopoiesis. Elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), confirmed the deranged type I immune responses. This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia. Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche. Antituberculosis treatment led to reversion of the aplastic crisis, disappearance of the atypical lymphocytes, increased marrow cellularity and 2 mo of hematological remission, providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis, the regression of leukemic cells and the activation of CD56+ atypical lymphocytes. Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state. However, the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode.
CONCLUSION Disseminated tuberculosis can induce CD56+ lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis, resulting in the development of aplastic crisis and leukemic cell regression.
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Affiliation(s)
- Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Dong Yang
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Jia Xu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
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18
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Ju B, Xiu NN, Xu J, Yang XD, Sun XY, Zhao XC. Flared inflammatory episode transforms advanced myelodysplastic syndrome into aplastic pancytopenia: A case report and literature review. World J Clin Cases 2023; 11:4105-4116. [PMID: 37388797 PMCID: PMC10303598 DOI: 10.12998/wjcc.v11.i17.4105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/21/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Myelodysplastic syndrome (MDS) is a hematological neoplasm, and an increase in myeloblasts is representative of leukemic hematopoiesis in advanced MDS. Low-risk MDS usually exhibits deranged autoimmunity resembling that of aplastic anemia (AA), whereas advanced MDS is characterized by a phenotype of immune exhaustion. MDS can be normo/hyperplastic or hypoplastic. Generally, bone marrow cellularity and myeloblasts increase with disease progression. Transformation from advanced MDS to AA-like syndrome with leukemic cell regression has not previously been reported.
CASE SUMMARY A middle-aged Chinese woman had a 4-year history of leukocytopenia. Six months prior to admission, the patient developed gradually worsening fatigue and performance status. The leukocytopenia further progressed. She was diagnosed with MDS with excess blasts-2 based on increased bone marrow cellularity and an increased percentage of myeloblasts on marrow and blood smears, an increased percentage of cluster of differentiation (CD)34+CD33+ progenitors in immunotyping analysis, a normal karyotype in cytogenetic analysis, and the identification of somatic mutations in CBL, KMT2D and NF1 in molecular analysis. Initially, neutropenia was the predominant hematological abnormality, with mild anemia and thrombocytosis, and the degree of fatigue was far more severe than the degree of anemia. In the following months, the patient experienced several febrile episodes. Intravenous antibiotic treatments were able to control the febrile episodes, but the elevated inflammatory indices persisted. The hematological parameters dramatically fluctuated with the waxing and waning of the inflammatory episodes. With recurrent flares of the inflammatory condition, agranulocytosis and severe anemia developed, with mild thrombocytopenia. During the patient’s hospitalization, computed tomography (CT) scans revealed the presence of extensive inflammatory lesions involving the lungs, mediastinum, pleura, gastrointestinal tract, peritoneum and urinary tract, with imaging features suggestive of the reactivation of disseminated tuberculosis. Reevaluation of the bone marrow smears revealed that the cellularity became hypoplastic, and the leukemic cells regressed, suggesting that both normal and leukemic hematopoiesis had been heavily suppressed. Immunological analysis of the bone marrow samples revealed a decreased percentage of CD34+ cells and an immunological signature resembling that of severe AA (SAA), confirming the regression of the leukemic cells by autoimmune-mediated attacks. The patient demonstrated resistance to multiple drugs, including antituberculotics, recombinant human granulocyte colony-stimulating factor, broad-spectrum antibiotics, voriconazole, ganciclovir, immune suppressants, eltrombopag and intravenous immunoglobulin, which further worsened the hematological injury and patient’s performance status. The patient eventually died of overwhelming infection and multidrug resistance.
CONCLUSION Advanced MDS can transform to aplastic cytopenia with leukemic cell regression and an immunological signature of SAA during inflammatory flare-ups.
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Affiliation(s)
- Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Nuan-Nuan Xiu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Jia Xu
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Dong Yang
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
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19
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Hong MH, Chang CK. [Mechanisms by which the bone marrow microenvironment of myelodysplastic neoplasms contributes to disease progression]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2023; 44:350-352. [PMID: 37357010 PMCID: PMC10282869 DOI: 10.3760/cma.j.issn.0253-2727.2023.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Indexed: 06/27/2023]
Affiliation(s)
- M H Hong
- Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - C K Chang
- Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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20
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Kelm JM, Pandey DS, Malin E, Kansou H, Arora S, Kumar R, Gavande NS. PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy. Mol Cancer 2023; 22:62. [PMID: 36991452 PMCID: PMC10061819 DOI: 10.1186/s12943-022-01707-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 12/23/2022] [Indexed: 03/31/2023] Open
Abstract
Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design.
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Affiliation(s)
- Jeremy M Kelm
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Deepti S Pandey
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Evan Malin
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Hussein Kansou
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA
| | - Sahil Arora
- Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Raj Kumar
- Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Navnath S Gavande
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences (EACPHS), Wayne State University, Detroit, MI, 48201, USA.
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
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21
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Zhou B, Liang S, Shang S, Li L. Association of TLR2 and TLR9 gene polymorphisms with atopic dermatitis: a systematic review and meta-analysis with trial sequential analysis. Immunol Med 2023; 46:32-44. [PMID: 36237117 DOI: 10.1080/25785826.2022.2132683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Atopic dermatitis (AD) is a chronic, inflammatory skin disease. The mechanism was complex. Genetic mutations of Toll-like receptor (TLR) may be associated with AD, yet still unclear. We aim to provide specific evidence of the association of TLR2, TLR9 gene polymorphisms with AD. Publications were selected according to the criteria. Newcastle-Ottawa Scale was applied to evaluate the quality. The value of ORs and 95%CIs were applied to measure the associations. According to the heterogeneity, the effects model of fixed or random was selected in data combination. For TLR2 gene rs5743708 polymorphism, under allele and recessive contrasts, the pooled data showed a significant correlation, which was A vs a, OR = 0.51 (95%CI: 0.30, 0.86); AA vs Aa + aa, OR = 0.54 (95%CI: 0.33, 0.88). For TLR2 gene rs4696480 polymorphism, under allele, homozygous, heterozygous, and dominant contrasts, the pooled data showed a significant correlation, which was A vs a, OR = 0.79 (95%CI: 0.64, 0.97), AA vs aa, OR = 0.65 (95%CI: 0.43, 0.97), Aa vs aa, OR = 0.68 (95%CI: 0.48, 0.97), AA + Aa vs aa, OR = 0.67 (95%CI: 0.49, 0.93). There are significant associations of TLR2 gene rs5743708, rs4696480 polymorphisms with atopic dermatitis, while no associations are found in TLR9 gene rs5743836, rs187084 polymorphisms.
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Affiliation(s)
- Boyang Zhou
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Surong Liang
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shuai Shang
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Linfeng Li
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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22
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Leśniak M, Lipniarska J, Majka P, Kopyt W, Lejman M, Zawitkowska J. The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies. Vaccines (Basel) 2023; 11:vaccines11020277. [PMID: 36851155 PMCID: PMC9967151 DOI: 10.3390/vaccines11020277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023] Open
Abstract
Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs-oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive effect of therapy with TRL agonists on the course of hemato-oncological diseases. Ligands impact activation of antigen-presenting cells which results in production of cytokines, transfer of mentioned cells to the lymphoid tissue and co-stimulatory surface molecules expression required for T-cell activation. Toll-like receptor agonists have already been used in oncology especially in the treatment of dermatological neoplastic lesions. The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines.
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Affiliation(s)
- Maria Leśniak
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Justyna Lipniarska
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Patrycja Majka
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Weronika Kopyt
- Student Scientific Society of Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
| | - Monika Lejman
- Independent Laboratory of Genetic Diagnostics, Medical University of Lublin, 20-093 Lublin, Poland
| | - Joanna Zawitkowska
- Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 20-093 Lublin, Poland
- Correspondence:
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23
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Li S, Yao JC, Oetjen KA, Krambs JR, Xia J, Zhang J, Schmidt AP, Helton NM, Fulton RS, Heath SE, Turnbull IR, Mbalaviele G, Ley TJ, Walter MJ, Link DC. IL-1β expression in bone marrow dendritic cells is induced by TLR2 agonists and regulates HSC function. Blood 2022; 140:1607-1620. [PMID: 35675516 PMCID: PMC9707400 DOI: 10.1182/blood.2022016084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/14/2022] [Indexed: 12/14/2022] Open
Abstract
Hematopoietic stem/progenitor cells (HSPCs) reside in localized microenvironments, or niches, in the bone marrow that provide key signals regulating their activity. A fundamental property of hematopoiesis is the ability to respond to environmental cues such as inflammation. How these cues are transmitted to HSPCs within hematopoietic niches is not well established. Here, we show that perivascular bone marrow dendritic cells (DCs) express a high basal level of Toll-like receptor-1 (TLR1) and TLR2. Systemic treatment with a TLR1/2 agonist induces HSPC expansion and mobilization. It also induces marked alterations in the bone marrow microenvironment, including a decrease in osteoblast activity and sinusoidal endothelial cell numbers. TLR1/2 agonist treatment of mice in which Myd88 is deleted specifically in DCs using Zbtb46-Cre show that the TLR1/2-induced expansion of multipotent HPSCs, but not HSPC mobilization or alterations in the bone marrow microenvironment, is dependent on TLR1/2 signaling in DCs. Interleukin-1β (IL-1β) is constitutively expressed in both murine and human DCs and is further induced after TLR1/2 stimulation. Systemic TLR1/2 agonist treatment of Il1r1-/- mice show that TLR1/2-induced HSPC expansion is dependent on IL-1β signaling. Single-cell RNA-sequencing of low-risk myelodysplastic syndrome bone marrow revealed that IL1B and TLR1 expression is increased in DCs. Collectively, these data suggest a model in which TLR1/2 stimulation of DCs induces secretion of IL-1β and other inflammatory cytokines into the perivascular niche, which in turn, regulates multipotent HSPCs. Increased DC TLR1/2 signaling may contribute to altered HSPC function in myelodysplastic syndrome by increasing local IL-1β expression.
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Affiliation(s)
- Sidan Li
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
- Hematology Oncology Center, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medial University, Beijing, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Juo-Chin Yao
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Karolyn A. Oetjen
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Joseph R. Krambs
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Jun Xia
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Jingzhu Zhang
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Amy P. Schmidt
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Nichole M. Helton
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Robert S. Fulton
- McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO
| | - Sharon E. Heath
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Isaiah R. Turnbull
- Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Gabriel Mbalaviele
- Division of Bone and Mineral Disease, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Timothy J. Ley
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Matthew J. Walter
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Daniel C. Link
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
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24
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Peng X, Zhu X, Di T, Tang F, Guo X, Liu Y, Bai J, Li Y, Li L, Zhang L. The yin-yang of immunity: Immune dysregulation in myelodysplastic syndrome with different risk stratification. Front Immunol 2022; 13:994053. [PMID: 36211357 PMCID: PMC9537682 DOI: 10.3389/fimmu.2022.994053] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid clonal diseases with diverse clinical courses, and immune dysregulation plays an important role in the pathogenesis of MDS. However, immune dysregulation is complex and heterogeneous in the development of MDS. Lower-risk MDS (LR-MDS) is mainly characterized by immune hyperfunction and increased apoptosis, and the immunosuppressive therapy shows a good response. Instead, higher-risk MDS (HR-MDS) is characterized by immune suppression and immune escape, and the immune activation therapy may improve the survival of HR-MDS. Furthermore, the immune dysregulation of some MDS changes dynamically which is characterized by the coexistence and mutual transformation of immune hyperfunction and immune suppression. Taken together, the authors think that the immune dysregulation in MDS with different risk stratification can be summarized by an advanced philosophical thought “Yin-Yang theory” in ancient China, meaning that the opposing forces may actually be interdependent and interconvertible. Clarifying the mechanism of immune dysregulation in MDS with different risk stratification can provide the new basis for diagnosis and clinical treatment. This review focuses on the manifestations and roles of immune dysregulation in the different risk MDS, and summarizes the latest progress of immunotherapy in MDS.
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Affiliation(s)
- Xiaohuan Peng
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xiaofeng Zhu
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Tianning Di
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Futian Tang
- Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Xiaojia Guo
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Yang Liu
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Jun Bai
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Yanhong Li
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
| | - Lijuan Li
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- *Correspondence: Lijuan Li, ; Liansheng Zhang,
| | - Liansheng Zhang
- Department of Hematology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- Key Laboratory of the Hematology of Gansu Province, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, China
- *Correspondence: Lijuan Li, ; Liansheng Zhang,
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25
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Association of Toll-like receptors polymorphisms with the risk of acute lymphoblastic leukemia in the Brazilian Amazon. Sci Rep 2022; 12:15159. [PMID: 36071076 PMCID: PMC9452670 DOI: 10.1038/s41598-022-19130-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children in childhood. Single-nucleotide polymorphism (SNPs) in key molecules of the immune system, such as Toll-like receptors (TLRs) and CD14 molecules, are associated with the development of several diseases. However, their role in ALL is unknown. A case–control study was performed with 152 ALL patients and 187 healthy individuals to investigate the role of SNPs in TLRs and the CD14 gene in ALL. In this study, TLR6 C > T rs5743810 [OR: 3.20, 95% CI: 1.11–9.17, p = 0.003) and TLR9 C > T rs187084 (OR: 2.29, 95% CI: 1.23–4.26, p = 0.000) seems to be a risk for development of ALL. In addition, the TLR1 T > G rs5743618 and TLR6 C > T rs5743810 polymorphisms with protection against death (OR: 0.17, 95% IC: 0.04–0.79, p = 0.008; OR: 0.48, 95% IC: 0.24–0.94, p = 0.031, respectively). Our results show that SNPs in TLRs genes may be involved in the pathogenesis of ALL and may influence clinical prognosis; however, further studies are necessary to elucidate the role of TLR1, TLR4, TLR5, TLR6, TLR9 and CD14 polymorphisms in this disease.
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26
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Inflammation and myeloid malignancy: Quenching the flame. Blood 2022; 140:1067-1074. [PMID: 35468199 DOI: 10.1182/blood.2021015162] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/22/2022] [Indexed: 01/19/2023] Open
Abstract
Chronic inflammation with aging ("inflammaging") plays a prominent role in the pathogenesis of myeloid malignancies. Aberrant inflammatory activity impacts many different cells in the marrow, including normal blood and stromal marrow elements and leukemic cells, in unique and distinct ways. Inflammation can promote selective clonal expansion through differential immune-mediated suppression of normal hematopoietic cells and malignant clones. We review these complex roles, how they can be understood by separating cell-intrinsic from extrinsic effects, and how this informs future clinical trials.
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27
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Lynch OF, Calvi LM. Immune Dysfunction, Cytokine Disruption, and Stromal Changes in Myelodysplastic Syndrome: A Review. Cells 2022; 11:580. [PMID: 35159389 PMCID: PMC8834462 DOI: 10.3390/cells11030580] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/12/2022] [Accepted: 01/27/2022] [Indexed: 02/04/2023] Open
Abstract
Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by bone marrow dysfunction and increased risk of transformation to leukemia. MDS represent complex and diverse diseases that evolve from malignant hematopoietic stem cells and involve not only the proliferation of malignant cells but also the dysfunction of normal bone marrow. Specifically, the marrow microenvironment-both hematopoietic and stromal components-is disrupted in MDS. While microenvironmental disruption has been described in human MDS and murine models of the disease, only a few current treatments target the microenvironment, including the immune system. In this review, we will examine current evidence supporting three key interdependent pillars of microenvironmental alteration in MDS-immune dysfunction, cytokine skewing, and stromal changes. Understanding the molecular changes seen in these diseases has been, and will continue to be, foundational to developing effective novel treatments that prevent disease progression and transformation to leukemia.
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Affiliation(s)
- Olivia F. Lynch
- School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA;
| | - Laura M. Calvi
- Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
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Abstract
PURPOSE OF REVIEW Cell intrinsic and extrinsic perturbations to inflammatory signaling pathways are a hallmark of development and progression of hematologic malignancies. The interleukin 1 receptor-associated kinases (IRAKs) are a family of related signaling intermediates (IRAK1, IRAK2, IRAK3, IRAK4) that operate at the nexus of multiple inflammatory pathways implicated in the hematologic malignancies. In this review, we explicate the oncogenic role of these kinases and review recent therapeutic advances in the dawning era of IRAK-targeted therapy. RECENT FINDINGS Emerging evidence places IRAK signaling at the confluence of adaptive resistance and oncogenesis in the hematologic malignancies and solid tissue tumors. Preclinical investigations nominate the IRAK kinases as targetable molecular dependencies in diverse cancers. SUMMARY IRAK-targeted therapies that have matriculated to early phase trials are yielding promising preliminary results. However, studies of IRAK kinase signaling continue to defy conventional signaling models and raise questions as to the design of optimal treatment strategies. Efforts to refine IRAK signaling mechanisms in the malignant context will inspire deliberate IRAK-targeted drug development and informed combination therapy.
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Affiliation(s)
- Joshua Bennett
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center
- Department of Cancer Biology
| | - Daniel T. Starczynowski
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center
- Department of Cancer Biology
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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29
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Comont T, Treiner E, Vergez F. From Immune Dysregulations to Therapeutic Perspectives in Myelodysplastic Syndromes: A Review. Diagnostics (Basel) 2021; 11:diagnostics11111982. [PMID: 34829329 PMCID: PMC8620222 DOI: 10.3390/diagnostics11111982] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022] Open
Abstract
The pathophysiology of myelodysplastic syndromes (MDSs) is complex and often includes immune dysregulation of both the innate and adaptive immune systems. Whereas clonal selection mainly involves smoldering inflammation, a cellular immunity dysfunction leads to increased apoptosis and blast proliferation. Addressing immune dysregulations in MDS is a recent concept that has allowed the identification of new therapeutic targets. Several approaches targeting the different actors of the immune system have therefore been developed. However, the results are very heterogeneous, indicating the need to improve our understanding of the disease and interactions between chronic inflammation, adaptive dysfunction, and somatic mutations. This review highlights current knowledge of the role of immune dysregulation in MDS pathophysiology and the field of new drugs.
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Affiliation(s)
- Thibault Comont
- Department of Internal Medicine, IUCT-Oncopole, Toulouse University Hospital (CHU-Toulouse), 31300 Toulouse, France
- Cancer Research Center of Toulouse, Unité Mixte de Recherche (UMR) 1037 INSERM, ERL5294 Centre National de La Recherche Scientifique, 31100 Toulouse, France;
- School of Medicine, Université Toulouse III—Paul Sabatier, 31062 Toulouse, France;
- Correspondence: ; Tel.: +33-531-15-62-66; Fax: +33-531-15-62-58
| | - Emmanuel Treiner
- School of Medicine, Université Toulouse III—Paul Sabatier, 31062 Toulouse, France;
- Laboratory of Immunology, Toulouse University Hospital (CHU-Toulouse), 31300 Toulouse, France
- Infinity, Inserm UMR1291, 31000 Toulouse, France
| | - François Vergez
- Cancer Research Center of Toulouse, Unité Mixte de Recherche (UMR) 1037 INSERM, ERL5294 Centre National de La Recherche Scientifique, 31100 Toulouse, France;
- School of Medicine, Université Toulouse III—Paul Sabatier, 31062 Toulouse, France;
- Laboratory of Hematology, IUCT-Oncopole, Toulouse University Hospital (CHU-Toulouse), 31300 Toulouse, France
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30
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Chashchina A, Märklin M, Hinterleitner C, Salih HR, Heitmann JS, Klimovich B. DNAM-1/CD226 is functionally expressed on acute myeloid leukemia (AML) cells and is associated with favorable prognosis. Sci Rep 2021; 11:18012. [PMID: 34504191 PMCID: PMC8429762 DOI: 10.1038/s41598-021-97400-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/20/2021] [Indexed: 11/09/2022] Open
Abstract
DNAM-1 is reportedly expressed on cytotoxic T and NK cells and, upon interaction with its ligands CD112 and CD155, plays an important role in tumor immunosurveillance. It has also been reported to be functionally expressed by myeloid cells, but expression and function on malignant cells of the myeloid lineage have not been studied so far. Here we analyzed expression of DNAM-1 in leukemic cells of acute myeloid leukemia (AML) patients. We found substantial levels of DNAM-1 to be expressed on leukemic blasts in 48 of 62 (> 75%) patients. Interaction of DNAM-1 with its ligands CD112 and CD155 induced release of the immunomodulatory cytokines IL-6, IL-8 IL-10 and TNF-α by AML cells and DNAM-1 expression correlated with a more differentiated phenotype. Multivariate analysis did not show any association of DNAM-1 positivity with established risk factors, but expression was significantly associated with clinical disease course: patients with high DNAM-1 surface levels had significantly longer progression-free and overall survival compared to DNAM-1low patients, independently whether patients had undergone allogenic stem cell transplantation or not. Together, our findings unravel a functional role of DNAM-1 in AML pathophysiology and identify DNAM-1 as a potential novel prognostic maker in AML.
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Affiliation(s)
- Anna Chashchina
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
| | - Clemens Hinterleitner
- DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany.,Department of Medical Oncology and Pulmonology, University Hospital Tübingen, 72076, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
| | - Jonas S Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany. .,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany.
| | - Boris Klimovich
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) Department of Internal Medicine, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,DFG Cluster of Excellence 2180 "Image-Guided and Functional Instructed Tumor Therapy (iFIT)", 72076, Tübingen, Germany
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Lyu C, Liu K, Jiang Y, Wang T, Wang Y, Xu R. Integrated analysis on mRNA microarray and microRNA microarray to screen immune-related biomarkers and pathways in myelodysplastic syndrome. ACTA ACUST UNITED AC 2021; 26:417-431. [PMID: 34130612 DOI: 10.1080/16078454.2021.1938429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Myelodysplastic syndrome (MDS) is a haematopoietic malignancy that is characterized by a heterogeneous clinical course and dysplastic maturation of blood lineages. Immune dysregulation has gained attention as one of the fundamental mechanisms responsible for the development of MDS. This study aimed to screen immune-related biomarkers and pathways in MDS. METHODS Differentially expressed mRNAs (DE-mRNAs) and differentially expressed microRNAs (DE-miRNAs) in different subtypes of MDS were sourced from the Gene Expression Omnibus (GEO) database. DE-mRNAs were intersected with immune-related gene sets to collect immune-related mRNAs, which were put into the Search Tool for the Retrieval of Interacting Genes (STRING) to construct protein-protein interaction (PPI) networks. Target mRNAs of DE-miRNAs were predicted using the miRDB database and intersected with screened immune-related mRNAs to construct miRNA-mRNA interaction networks. Topological analysis of constructed networks was applied to screen key molecules, which were assessed in independent datasets and previous literature. Enrichment analysis was applied to screen dysregulated pathways in MDS. RESULTS Screened key mRNAs were mainly from the Toll-like receptor (TLR) family, including TLR2, TLR4, TLR7, and from the chemokine family, including C-X-C motif chemokine ligand 10 (CXCL10) and CC chemokine ligand 4 (CCL4). Cytokine-cytokine receptor interactions were among the major pathways in the enrichment analysis results. Hsa-miR-30b, hsa-miR-30e and hsa-miR-221 were validated as key miRNAs and modulate cytokine-cytokine receptor interactions by targeting immune-related mRNAs. CONCLUSION Dysregulated cytokines reflect the immunization status in MDS. Immune-related miRNA-mRNA interactions not only provide a perspective to our understanding of immunologic derangement in the pathogenesis of MDS but also provide new therapeutic opportunities.
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Affiliation(s)
- Chunyi Lyu
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Kui Liu
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Yuehua Jiang
- Central Laboratory of Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Teng Wang
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Yan Wang
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.,Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Ruirong Xu
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.,Shandong Provincial Health Commission Key Laboratory of Hematology of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
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Trowbridge JJ, Starczynowski DT. Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS. J Exp Med 2021; 218:212382. [PMID: 34129017 PMCID: PMC8210621 DOI: 10.1084/jem.20201544] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/23/2022] Open
Abstract
With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.
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Affiliation(s)
| | - Daniel T Starczynowski
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.,Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH
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Pathogenic Roles of S100A8 and S100A9 Proteins in Acute Myeloid and Lymphoid Leukemia: Clinical and Therapeutic Impacts. Molecules 2021; 26:molecules26051323. [PMID: 33801279 PMCID: PMC7958135 DOI: 10.3390/molecules26051323] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/10/2021] [Accepted: 02/18/2021] [Indexed: 02/06/2023] Open
Abstract
Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). These deregulations impact the prognosis of patients through various mechanisms of cellular or extracellular regulation of the viability of leukemic cells. In particular, S100A8 and S100A9 in monomeric, homodimeric, or heterodimeric forms are able to modulate the survival and the sensitivity to chemotherapy of leukemic clones through their action on the regulation of intracellular calcium, on oxidative stress, on the activation of apoptosis, and thanks to their implications, on cell death regulation by autophagy and pyroptosis. Moreover, biologic effects of S100A8/9 via both TLR4 and RAGE on hematopoietic stem cells contribute to the selection and expansion of leukemic clones by excretion of proinflammatory cytokines and/or immune regulation. Hence, the therapeutic targeting of S100A8 and S100A9 appears to be a promising way to improve treatment efficiency in acute leukemias.
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Vilchis-Ordoñez A, Ramírez-Ramírez D, Pelayo R. The triad inflammation-microenvironment-tumor initiating cells in leukemia progression. CURRENT OPINION IN PHYSIOLOGY 2021. [DOI: 10.1016/j.cophys.2020.10.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Najafi S, Ghanavat M, Shahrabi S, Gatavizadeh Z, Saki N. The effect of inflammatory factors and their inhibitors on the hematopoietic stem cells fate. Cell Biol Int 2021; 45:900-912. [PMID: 33386770 DOI: 10.1002/cbin.11545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 12/02/2020] [Accepted: 12/25/2020] [Indexed: 11/12/2022]
Abstract
Inflammatory cytokines exert different effects on hematopoietic stem cells (HSCs), lead to the development of various cell lineages in bone marrow (BM) and are thus a differentiation axis for HSCs. The content used in this article has been obtained by searching PubMed database and Google Scholar search engine of English-language articles (1995-2020) using "Hematopoietic stem cell," "Inflammatory cytokine," "Homeostasis," and "Myelopoiesis." Inflammatory cytokines are involved in the differentiation and proliferation of hematopoietic progenitors to compensate for cellular death due to inflammation. Since each of these cytokines differentiates HSCs into a specific cell line, the difference in the effect of these cytokines on the fate of HSC progenitors can be predicted. Inhibitors of these cytokines can also control the inflammatory process as well as the cells involved in leukemic conditions. In general, inflammatory signaling can specify the dominant cell line in BM to counteract inflammation and leukemic condition via stimulating or inhibiting hematopoietic progenitors. Therefore, detection of the effects of inflammatory cytokines on the differentiation of HSCs can be an appropriate approach to check inflammatory and leukemic conditions and the suppression of these cytokines by their inhibitors allows for control of homeostasis in stressful conditions.
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Affiliation(s)
- Sahar Najafi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Ghanavat
- Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saied Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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Zhao XC, Sun XY, Ju B, Meng FJ, Zhao HG. Acquired aplastic anemia: Is bystander insult to autologous hematopoiesis driven by immune surveillance against malignant cells? World J Stem Cells 2020; 12:1429-1438. [PMID: 33312408 PMCID: PMC7705466 DOI: 10.4252/wjsc.v12.i11.1429] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 09/20/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023] Open
Abstract
We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations (GCPs). This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments, with each recurrence occurring 7-8 wk from a GCP. After his third recurrence, he was prescribed successive treatment with rifampicin, berberine, and monthly administered GCP for 4 mo, and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy, and eventually died of septic shock. Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis. From the treatment process and laboratory investigations, it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state. Incorporation of rifampicin, berberine, and monthly GCP into cyclosporine can enhance the immunosuppressive effect. In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure, the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.
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Affiliation(s)
- Xi-Chen Zhao
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Xiao-Yun Sun
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Bo Ju
- Department of Hematology, The Central Hospital of Qingdao West Coast New Area, Qingdao 266555, Shandong Province, China
| | - Fan-Jun Meng
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Hong-Guo Zhao
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
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