|
1
|
Madigan LM, Boggs NA, Rets AV, Gru AA, Tashi T, Wada DA, Florell SR, Carter MC. Mastocytosis in the Skin: Approach to Diagnosis, Evaluation, and Management in Adult and Pediatric Patients. Am J Clin Dermatol 2025:10.1007/s40257-025-00947-7. [PMID: 40392511 DOI: 10.1007/s40257-025-00947-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 05/22/2025]
Abstract
Mastocytosis is characterized by the clonal infiltration and proliferation of neoplastic mast cells into target organs. Clinical features of mastocytosis are based in large part on dysregulated mast cell mediator release. Affected individuals may present with isolated skin involvement or multisystemic disease with a spectrum of symptoms including anaphylaxis, pathologic fractures, and chronic gastrointestinal, neurocognitive, musculoskeletal, and constitutional symptoms. The term "mastocytosis in the skin" refers to individuals with cutaneous infiltration and encompasses both localized and systemic forms of disease. Cutaneous involvement is further categorized into cutaneous mastocytoma, diffuse cutaneous mastocytosis, and maculopapular cutaneous mastocytosis based on morphology. In ~95% of patients with systemic mastocytosis, the disease is driven by the KIT D816V somatic variant. The aim of this clinical review is to highlight the diagnostic considerations, management complexities, and evolving treatment landscape that must be considered when evaluating a patient presenting with mastocytosis in their skin. Clinical manifestations, histopathology, and laboratory parameters are essential to diagnosis and determining the disease burden in those with known or suspected systemic mastocytosis. Once appropriately staged, both skin-directed therapy as well as novel systemic treatment options, including selective tyrosine kinase inhibitors, can be considered with the potential to improve patient outcomes.
Collapse
Affiliation(s)
- Lauren M Madigan
- Department of Dermatology, University of Utah Health, HELIX Building Level 1 South, 30 N. Mario Capecchi Drive, Salt Lake City, UT, 84112, USA.
| | - Nathan A Boggs
- Allergy and Immunology Service, Walter Reed National Military Medical Center, Bethesda, MD, USA
- Department of Medicine, Uniformed Services University, Bethesda, MD, USA
| | - Anton V Rets
- ARUP Laboratories, Salt Lake City, UT, USA
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Alejandro A Gru
- Department of Dermatology, Columbia University, New York City, NY, USA
| | - Tsewang Tashi
- Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - David A Wada
- Department of Dermatology, University of Utah Health, HELIX Building Level 1 South, 30 N. Mario Capecchi Drive, Salt Lake City, UT, 84112, USA
- Huntsman Cancer Institute, Salt Lake City, UT, USA
| | - Scott R Florell
- Departments of Dermatology, and Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Melody C Carter
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
2
|
Akin C, Arock M, Carter MC, George TI, Valent P. Mastocytosis. Nat Rev Dis Primers 2025; 11:30. [PMID: 40274818 DOI: 10.1038/s41572-025-00611-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/21/2025] [Indexed: 04/26/2025]
Abstract
Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems. The disease is divided into cutaneous mastocytosis, systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms. The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favourable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor. During the past 15 years, major advances have been made in the diagnosis, prognosis and management of patients with mast cell neoplasms. Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis. The preclinical and clinical development of KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients.
Collapse
Affiliation(s)
- Cem Akin
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
| | - Michel Arock
- CEREMAST, Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), Paris, France
| | - Melody C Carter
- Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA
| | - Tracy I George
- Department of Pathology, University of Utah, Salt Lake City, UT, USA
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
- Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
3
|
Li Z, Schneikert J, Tripathi SR, Jin M, Bal G, Zuberbier T, Babina M. CREB Is Critically Implicated in Skin Mast Cell Degranulation Elicited via FcεRI and MRGPRX2. Cells 2024; 13:1681. [PMID: 39451199 PMCID: PMC11506305 DOI: 10.3390/cells13201681] [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: 07/06/2024] [Revised: 09/23/2024] [Accepted: 10/08/2024] [Indexed: 10/26/2024] Open
Abstract
Skin mast cells (MCs) mediate acute allergic reactions in the cutaneous environment and contribute to chronic dermatoses, including urticaria, and atopic or contact dermatitis. The cAMP response element binding protein (CREB), an evolutionarily well conserved transcription factor (TF) with over 4,000 binding sites in the genome, was recently found to form a feedforward loop with KIT, maintaining MC survival. The most selective MC function is degranulation with its acute release of prestored mediators. Herein, we asked whether CREB contributes to the expression and function of the degranulation-competent receptors FcεRI and MRGPRX2. Interference with CREB by pharmacological inhibition (CREBi, 666-15) or RNA interference only slightly affected the expression of these receptors, while KIT was strongly attenuated. Interestingly, MRGPRX2 surface expression moderately increased following CREB-knockdown, whereas MRGPRX2-dependent exocytosis simultaneously decreased. FcεRI expression and function were regulated consistently, although the effect was stronger at the functional level. Preformed MC mediators (tryptase, histamine, β-hexosaminidase) remained comparable following CREB attenuation, suggesting that granule synthesis did not rely on CREB function. Collectively, in contrast to KIT, FcεRI and MRGPRX2 moderately depend on unperturbed CREB function. Nevertheless, CREB is required to maintain MC releasability irrespective of stimulus, insinuating that CREB may operate by safeguarding the degranulation machinery. To our knowledge, CREB is the first factor identified to regulate MRGPRX2 expression and function in opposite direction. Overall, the ancient TF is an indispensable component of skin MCs, orchestrating not only survival and proliferation but also their secretory competence.
Collapse
Affiliation(s)
- Zhuoran Li
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Jean Schneikert
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Shiva Raj Tripathi
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Manqiu Jin
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Gürkan Bal
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Torsten Zuberbier
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Magda Babina
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (Z.L.); (J.S.); (S.R.T.); (M.J.); (G.B.); (T.Z.)
- Institute of Allergology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| |
Collapse
|
|
4
|
Sabato V, Beyens M, Toscano A, Van Gasse A, Ebo DG. Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes. Curr Allergy Asthma Rep 2024; 24:63-71. [PMID: 38217824 DOI: 10.1007/s11882-023-01123-9] [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] [Accepted: 12/28/2023] [Indexed: 01/15/2024]
Abstract
PURPOSE OF REVIEW Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS). RECENT FINDINGS Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.
Collapse
Affiliation(s)
- Vito Sabato
- Department of Immunology, Allergology, Rheumatology, The Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken T5.9582 Universiteitsplein 1, 2610, Antwerp, Belgium
- Antwerp University Hospital, Edegem, Belgium
| | - Michiel Beyens
- Department of Immunology, Allergology, Rheumatology, The Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken T5.9582 Universiteitsplein 1, 2610, Antwerp, Belgium
- Antwerp University Hospital, Edegem, Belgium
| | - Alessandro Toscano
- Department of Immunology, Allergology, Rheumatology, The Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken T5.9582 Universiteitsplein 1, 2610, Antwerp, Belgium
- Antwerp University Hospital, Edegem, Belgium
| | - Athina Van Gasse
- Department of Paediatrics, The Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - Didier G Ebo
- Department of Immunology, Allergology, Rheumatology, The Infla-Med Centre of Excellence, Faculty of Medicine and Health Sciences, University of Antwerp, Campus Drie Eiken T5.9582 Universiteitsplein 1, 2610, Antwerp, Belgium.
- Antwerp University Hospital, Edegem, Belgium.
| |
Collapse
|
|
5
|
Bal G, Schneikert J, Li Z, Franke K, Tripathi SR, Zuberbier T, Babina M. CREB Is Indispensable to KIT Function in Human Skin Mast Cells-A Positive Feedback Loop between CREB and KIT Orchestrates Skin Mast Cell Fate. Cells 2023; 13:42. [PMID: 38201246 PMCID: PMC10778115 DOI: 10.3390/cells13010042] [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: 11/29/2023] [Revised: 12/18/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Skin mast cells (MCs) are critical effector cells in acute allergic reactions, and they contribute to chronic dermatoses like urticaria and atopic and contact dermatitis. KIT represents the cells' crucial receptor tyrosine kinase, which orchestrates proliferation, survival, and functional programs throughout the lifespan. cAMP response element binding protein (CREB), an evolutionarily well-conserved transcription factor (TF), regulates multiple cellular programs, but its function in MCs is poorly understood. We recently reported that CREB is an effector of the SCF (Stem Cell Factor)/KIT axis. Here, we ask whether CREB may also act upstream of KIT to orchestrate its functioning. Primary human MCs were isolated from skin and cultured in SCF+IL-4 (Interleukin-4). Pharmacological inhibition (666-15) and RNA interference served to manipulate CREB function. We studied KIT expression using flow cytometry and RT-qPCR, KIT-mediated signaling using immunoblotting, and cell survival using scatterplot and caspase-3 activity. The proliferation and cycle phases were quantified following BrdU incorporation. Transient CREB perturbation resulted in reduced KIT expression. Conversely, microphthalmia transcription factor (MITF) was unnecessary for KIT maintenance. KIT attenuation secondary to CREB was associated with heavily impaired KIT functional outputs, like anti-apoptosis and cell cycle progression. Likewise, KIT-elicited phosphorylation of ERK1/2 (Extracellular Signal-Regulated Kinase 1/2), AKT, and STAT5 (Signal Transducer and Activator of Transcription) was substantially diminished upon CREB inhibition. Surprisingly, the longer-term interference of CREB led to complete cell elimination, in a way surpassing KIT inhibition. Collectively, we reveal CREB as non-redundant in MCs, with its absence being incompatible with skin MCs' existence. Since SCF/KIT regulates CREB activity and, vice versa, CREB is required for KIT function, a positive feedforward loop between these elements dictates skin MCs' fate.
Collapse
Affiliation(s)
- Gürkan Bal
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Jean Schneikert
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Zhuoran Li
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Kristin Franke
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Shiva Raj Tripathi
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Torsten Zuberbier
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Magda Babina
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany; (G.B.); (J.S.); (Z.L.); (K.F.); (S.R.T.); (T.Z.)
- Institute of Allergology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
| |
Collapse
|
|
6
|
Costa A, Scalzulli E, Carmosino I, Capriata M, Ielo C, Masucci C, Passucci M, Martelli M, Breccia M. Systemic mastocytosis: 2023 update on diagnosis and management in adults. Expert Opin Emerg Drugs 2023; 28:153-165. [PMID: 37256917 DOI: 10.1080/14728214.2023.2221028] [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: 04/11/2023] [Revised: 05/27/2023] [Accepted: 05/30/2023] [Indexed: 06/02/2023]
Abstract
INTRODUCTION Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World Health Organization (WHO) and the International Consensus Classification (ICC) modified the diagnostic and classification criteria of SM. Moreover, the identification of new clinical and molecular variables has improved prognostic tools and led to increasingly individualized therapeutic strategies. AREAS COVERED The aim of this review is to present the updates introduced by the International Consensus Classification in diagnostic criteria of SM. In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib. EXPERT OPINION Diagnosis and classification of SM has evolved over years. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future.
Collapse
Affiliation(s)
- Alessandro Costa
- Hematology Unit, Businco Hospital, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Emilia Scalzulli
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Ida Carmosino
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Marcello Capriata
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Claudia Ielo
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Chiara Masucci
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Mauro Passucci
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Maurizio Martelli
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| | - Massimo Breccia
- Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Rome, Italy
| |
Collapse
|
|
7
|
Abstract
Systemic mastocytosis is associated with KIT D816V mutation in more than 90% of cases. Patients with non-advanced forms of mastocytosis (indolent systemic mastocytosis, bone marrow mastocytosis, and smoldering systenic mastocytosis) have a low rate of progession to advanced variants and generally have a comparable life expectancy to age-matched general population. Symptomatology in non-advanced mastocytosis is variable and is related to mast cell mediator release. While some patients require no or minimal symptomatic therapy with antimediator drugs, other may suffer from refractory symptoms impacting the quality of life despite being on multiple anti-mediator drugs. KIT tyrosine kinase inhibitors have been approved for advanced SM, and avapritinib has also been recently approved as the first such inhibitor for indolent systemic mastocytosis. Other TKIs are currently in clinical trials for patients with non-advanced SM who have persistent and severe symptoms despite optimized antimediator therapy. This article will review the current state of the science and available clinical data from trials of tyrosine kinase inhibitors in non-advanced systemic mastocytosis.
Collapse
Affiliation(s)
- Cem Akin
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, PO Box 442, Suite H-2100, Ann Arbor, MI 48106-0442, USA.
| |
Collapse
|
|
8
|
Jiang M, Vadas P. Hereditary alpha-tryptasemia and complete deletion of exon 8 of the c-kit gene in patients with mast cell activation syndrome. Leuk Lymphoma 2023; 64:1348-1351. [PMID: 37086476 DOI: 10.1080/10428194.2023.2203286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/16/2023] [Accepted: 04/11/2023] [Indexed: 04/24/2023]
Affiliation(s)
- Maggie Jiang
- Division of Allergy and Clinical Immunology, St. Michael's Hospital/University of Toronto, Toronto, Canada
| | - Peter Vadas
- Division of Allergy and Clinical Immunology, St. Michael's Hospital/University of Toronto, Toronto, Canada
| |
Collapse
|
|
9
|
Dispenza MC, Metcalfe DD, Olivera A. Research Advances in Mast Cell Biology and Their Translation Into Novel Therapies for Anaphylaxis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:2032-2042. [PMID: 36958519 PMCID: PMC10330051 DOI: 10.1016/j.jaip.2023.03.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/07/2023] [Accepted: 03/08/2023] [Indexed: 03/25/2023]
Abstract
Anaphylaxis is an acute, potentially life-threatening systemic allergic reaction for which there are no known reliable preventative therapies. Its primary cell mediator, the mast cell, has several pathophysiologic roles and functions in IgE-mediated reactions that continue to be poorly understood. Recent advances in the understanding of allergic mechanisms have identified novel targets for inhibiting mast cell function and activation. The prevention of anaphylaxis is within reach with new drugs that could modulate immune tolerance, mast cell proliferation and differentiation, and IgE regulation and production. Several US Food and Drug Administration-approved drugs for chronic urticaria, mastocytosis, and cancer are also being repurposed to prevent anaphylaxis. New therapeutics have not only shown promise in potential efficacy for preventing IgE-mediated reactions, but in some cases, they are able to inform us about mast cell mechanisms in vivo. This review summarizes the most recent advances in the treatment of anaphylaxis that have arisen from new pharmacologic tools and our current understanding of mast cell biology.
Collapse
Affiliation(s)
- Melanie C Dispenza
- Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
| | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergy Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Ana Olivera
- Mast Cell Biology Section, Laboratory of Allergy Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| |
Collapse
|
|
10
|
Franke K, Bal G, Li Z, Zuberbier T, Babina M. Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells. Cells 2023; 12:cells12091306. [PMID: 37174705 PMCID: PMC10177086 DOI: 10.3390/cells12091306] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/20/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Mast cells (MCs) are key effector cells in allergic and inflammatory diseases, and the SCF/KIT axis regulates most aspects of the cells' biology. Using terminally differentiated skin MCs, we recently reported on proteome-wide phosphorylation changes initiated by KIT dimerization. C1orf186/RHEX was revealed as one of the proteins to become heavily phosphorylated. Its function in MCs is undefined and only some information is available for erythroblasts. Using public databases and our own data, we now report that RHEX exhibits highly restricted expression with a clear dominance in MCs. While expression is most pronounced in mature MCs, RHEX is also abundant in immature/transformed MC cell lines (HMC-1, LAD2), suggesting early expression with further increase during differentiation. Using RHEX-selective RNA interference, we reveal that RHEX unexpectedly acts as a negative regulator of SCF-supported skin MC survival. This finding is substantiated by RHEX's interference with KIT signal transduction, whereby ERK1/2 and p38 both were more strongly activated when RHEX was attenuated. Comparing RHEX and capicua (a recently identified repressor) revealed that each protein preferentially suppresses other signaling modules elicited by KIT. Induction of immediate-early genes strictly requires ERK1/2 in SCF-triggered MCs; we now demonstrate that RHEX diminution translates to this downstream event, and thereby enhances NR4A2, JUNB, and EGR1 induction. Collectively, our study reveals RHEX as a repressor of KIT signaling and function in MCs. As an abundant and selective lineage marker, RHEX may have various roles in the lineage, and the provided framework will enable future work on its involvement in other crucial processes.
Collapse
Affiliation(s)
- Kristin Franke
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Gürkan Bal
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Zhuoran Li
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Torsten Zuberbier
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Magda Babina
- Institute of Allergology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Hindenburgdamm 30, 12203 Berlin, Germany
| |
Collapse
|
|
11
|
Rama TA, Torrado I, Henriques AF, Sánchez-Muñoz L, Jara-Acevedo M, Navarro-Navarro P, Caldas C, Mayado A, Muñoz-González J, García-Montero A, Mollejo M, Redondo E, Garbán A, Moreira A, Órfão A, Álvarez-Twose I. Mast Cell Activation Syndromes: Comparison Between Two Scoring Models to Predict for Mast Cell Clonality. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:908-919.e4. [PMID: 36535520 DOI: 10.1016/j.jaip.2022.11.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 10/24/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND The Red Española de Mastocitosis (Spanish Network on Mastocytosis) score (REMAs) and the National Institutes of Health idiopathic clonal anaphylaxis score (NICAS) were developed for more efficient screening of mast cell (MC) clonality in MC activation syndromes. In a limited idiopathic anaphylaxis case series, the NICAS showed higher accuracy compared with the REMAs. OBJECTIVE To compare the performance of the REMAs against the NICAS in the diagnosis of MC clonality. METHODS We compared the diagnostic value of the REMAs against the NICAS in 182 patients (63% men, median age 56 years) who presented with anaphylaxis triggered by Hymenoptera venom allergy (45%), drugs (15%), food (11%), idiopathic anaphylaxis (20%), and mixed causes (10%). KIT mutation was assessed in parallel in whole blood and bone marrow (BM) and, when negative, in highly purified BM MC. TPSAB1 was genotyped in a subset of 71 patients. RESULTS We found higher accuracy and rates of correctly classified patients for the REMAs (82% and 84%) compared with the NICAS (75% and 75%; P = .02 and P = .03, respectively), particularly among men (P = .05), patients with systemic mastocytosis (P = .05), those presenting anaphylaxis owing to any cause featuring urticaria (P = .04), cardiovascular symptoms (P = .02), and/or presyncope (P = .02) and those with a blood-negative/BM-positive KIT mutational profile (P = .002), but not hereditary α-tryptasemia-associated genotypes. Combined assessment of the REMAs and KITD816V in blood yielded an overall improved classification efficiency of 86% versus 84% for REMAs. CONCLUSIONS The combined use of the REMAs and blood detection of KITD816V is recommended, but more sensitive blood-based molecular assays to detect KITD816V are needed.
Collapse
Affiliation(s)
- Tiago Azenha Rama
- Serviço de Imunoalergologia, Centro Hospitalar Universitário São João, Porto, Portugal; Serviço de Imunologia Básica e Clínica, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; EPIUnit, Institute of Public Health, University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - Inés Torrado
- Instituto de Estudios de Mastocitosis de Castilla La Mancha, Reference Center for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain
| | - Ana Filipa Henriques
- Instituto de Estudios de Mastocitosis de Castilla La Mancha, Reference Center for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis, Toledo and Salamanca, Spain
| | - Laura Sánchez-Muñoz
- Instituto de Estudios de Mastocitosis de Castilla La Mancha, Reference Center for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Jara-Acevedo
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; DNA Sequencing Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Paula Navarro-Navarro
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; DNA Sequencing Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Carolina Caldas
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; DNA Sequencing Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Andrea Mayado
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center, Department of Medicine, Cytometry Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Javier Muñoz-González
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center, Department of Medicine, Cytometry Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Andrés García-Montero
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center, Department of Medicine, Cytometry Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Manuela Mollejo
- Pathology Department, Hospital Virgen de la Salud, Complejo Hospitalario Universitario de Toledo, Toledo, Spain
| | - Elba Redondo
- Servicio de Alergologia, Hospital Clínico San Carlos, Madrid, Spain
| | - Andrea Garbán
- Servicio de Alergologia, Hospital Clínico San Carlos, Madrid, Spain
| | - André Moreira
- Serviço de Imunoalergologia, Centro Hospitalar Universitário São João, Porto, Portugal; Serviço de Imunologia Básica e Clínica, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; EPIUnit, Institute of Public Health, University of Porto, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
| | - Alberto Órfão
- Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain; Cancer Research Center, Department of Medicine, Cytometry Service, Instituto de Investigación Biomédica de Salamanca, University of Salamanca, Salamanca, Spain
| | - Iván Álvarez-Twose
- Instituto de Estudios de Mastocitosis de Castilla La Mancha, Reference Center for Mastocytosis, Hospital Virgen del Valle, Complejo Hospitalario Universitario de Toledo, Toledo, Spain; Spanish Network on Mastocytosis, Toledo and Salamanca, Spain; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid, Spain.
| |
Collapse
|
|
12
|
CREB Is Activated by the SCF/KIT Axis in a Partially ERK-Dependent Manner and Orchestrates Survival and the Induction of Immediate Early Genes in Human Skin Mast Cells. Int J Mol Sci 2023; 24:ijms24044135. [PMID: 36835547 PMCID: PMC9966046 DOI: 10.3390/ijms24044135] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/27/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
cAMP response element binding protein (CREB) functions as a prototypical stimulus-inducible transcription factor (TF) that initiates multiple cellular changes in response to activation. Despite pronounced expression in mast cells (MCs), CREB function is surprisingly ill-defined in the lineage. Skin MCs (skMCs) are critical effector cells in acute allergic and pseudo-allergic settings, and they contribute to various chronic dermatoses such as urticaria, atopic dermatitis, allergic contact dermatitis, psoriasis, prurigo, rosacea and others. Using MCs of skin origin, we demonstrate herein that CREB is rapidly phosphorylated on serine-133 upon SCF-mediated KIT dimerization. Phosphorylation initiated by the SCF/KIT axis required intrinsic KIT kinase activity and partially depended on ERK1/2, but not on other kinases such as p38, JNK, PI3K or PKA. CREB was constitutively nuclear, where phosphorylation occurred. Interestingly, ERK did not translocate to the nucleus upon SCF activation of skMCs, but a fraction was present in the nucleus at baseline, and phosphorylation was prompted in the cytoplasm and nucleus in situ. CREB was required for SCF-facilitated survival, as demonstrated with the CREB-selective inhibitor 666-15. Knock-down of CREB by RNA interference duplicated CREB's anti-apoptotic function. On comparison with other modules (PI3K, p38 and MEK/ERK), CREB was equal or more potent at survival promotion. SCF efficiently induces immediate early genes (IEGs) in skMCs (FOS, JUNB and NR4A2). We now demonstrate that CREB is an essential partaker in this induction. Collectively, the ancient TF CREB is a crucial component of skMCs, where it operates as an effector of the SCF/KIT axis, orchestrating IEG induction and lifespan.
Collapse
|
|
13
|
Franke K, Kirchner M, Mertins P, Zuberbier T, Babina M. The SCF/KIT axis in human mast cells: Capicua acts as potent KIT repressor and ERK predominates PI3K. Allergy 2022; 77:3337-3349. [PMID: 35652819 DOI: 10.1111/all.15396] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 04/28/2022] [Accepted: 05/11/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND The SCF/KIT axis regulates nearly all aspects of mast cell (MC) biology. A comprehensive view of SCF-triggered phosphorylation dynamics is lacking. The relationship between signaling modules and SCF-supported functions likewise remains ill-defined. METHODS Mast cells were isolated from human skin; upon stimulation by SCF, global phosphoproteomic changes were analyzed by LC-MS/MS and selectively validated by immunoblotting. MC survival was inspected by YoPro; BrdU incorporation served to monitor proliferation. Gene expression was quantified by RT-qPCR and cytokines by ELISA. Pharmacological inhibitors were supplemented by ERK1 and/or ERK2 knockdown. CIC translocation and degradation were studied in nuclear and cytoplasmic fractions. CIC's impact on KIT signaling and function was assessed following RNA interference. RESULTS ≈5400 out of ≈10,500 phosphosites experienced regulation by SCF. The MEK/ERK cascade was strongly induced surpassing STAT5 > PI3K/Akt > p38 > JNK. Comparison between MEK/ERK's and PI3K's support of basic programs (apoptosis, proliferation) revealed equipotency between modules. In functional outputs (gene expression, cytokines), ERK was the most influential kinase. OSM and LIF production was identified in skin MCs. Strikingly, SCF triggered massive phosphorylation of a protein not associated with KIT previously: CIC. Phosphorylation was followed by CIC's cytoplasmic appearance and degradation, the latter sensitive to protease but not preoteasome inhibition. Both shuttling and degradation were ERK-dependent. Conversely, CIC-siRNA facilitated KIT signaling, functional outputs, and survival. CONCLUSION The SCF/KIT axis shows notable strength in MCs, and MEK/ERK as most prominent module. An inhibitory circuit exists between KIT and CIC. CIC stabilization in MCs may turn out as a therapeutic option to interfere with allergic and MC-driven diseases.
Collapse
Affiliation(s)
- Kristin Franke
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Berlin, Germany
| | - Marieluise Kirchner
- Core Unit Proteomics, Berlin Institute of Health at Charité- Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
| | - Philipp Mertins
- Core Unit Proteomics, Berlin Institute of Health at Charité- Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany
| | - Torsten Zuberbier
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Berlin, Germany
| | - Magda Babina
- Institute of Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, Berlin, Germany
| |
Collapse
|
|
14
|
Vaseghi-Shanjani M, Snow AL, Margolis DJ, Latrous M, Milner JD, Turvey SE, Biggs CM. Atopy as Immune Dysregulation: Offender Genes and Targets. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2022; 10:1737-1756. [PMID: 35680527 DOI: 10.1016/j.jaip.2022.04.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/06/2022] [Accepted: 04/06/2022] [Indexed: 06/15/2023]
Abstract
Allergic diseases are a heterogeneous group of disorders resulting from exaggerated type 2 inflammation. Although typically viewed as polygenic multifactorial disorders caused by the interaction of several genes with the environment, we have come to appreciate that allergic diseases can also be caused by monogenic variants affecting the immune system and the skin epithelial barrier. Through a myriad of genetic association studies and high-throughput sequencing tools, many monogenic and polygenic culprits of allergic diseases have been described. Identifying the genetic causes of atopy has shaped our understanding of how these conditions occur and how they may be treated and even prevented. Precision diagnostic tools and therapies that address the specific molecular pathways implicated in allergic inflammation provide exciting opportunities to improve our care for patients across the field of allergy and immunology. Here, we highlight offender genes implicated in polygenic and monogenic allergic diseases and list targeted therapeutic approaches that address these disrupted pathways.
Collapse
Affiliation(s)
- Maryam Vaseghi-Shanjani
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrew L Snow
- Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Md
| | - David J Margolis
- Department of Dermatology and Dermatologic Surgery, University of Pennsylvania Medical Center, Philadelphia, Pa; Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Medical Center, Philadelphia, Pa
| | - Meriem Latrous
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Joshua D Milner
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
| | - Stuart E Turvey
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Experimental Medicine Program, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Catherine M Biggs
- Department of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; St Paul's Hospital, Vancouver, British Columbia, Canada.
| |
Collapse
|
|
15
|
Akin C, Arock M, Valent P. Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: are we there yet? J Allergy Clin Immunol 2022; 149:1912-1918. [PMID: 35487307 DOI: 10.1016/j.jaci.2022.04.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/21/2022] [Accepted: 04/21/2022] [Indexed: 10/18/2022]
Abstract
Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms In a small number of patients, hematologic progression is seen in the follow up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MC in ISM. Since MC in over 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The two such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even non-effective against KIT D816V and are thus only recommended for use in patients with other KIT mutant forms (non codon 816 mutations) or with wild type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat ISM patients should be balanced against their toxicity and short and long term safety.
Collapse
Affiliation(s)
- Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Charles-Foix Hospital, AP-HP Sorbonne University, Paris, France
| | - Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria
| |
Collapse
|
|
16
|
Valent P, Akin C, Hartmann K, Reiter A, Gotlib J, Sotlar K, Sperr WR, Degenfeld-Schonburg L, Smiljkovic D, Triggiani M, Horny HP, Arock M, Galli SJ, Metcalfe DD. Drug-Induced Mast Cell Eradication: A Novel Approach to Treat Mast Cell Activation Disorders? J Allergy Clin Immunol 2022; 149:1866-1874. [PMID: 35421448 DOI: 10.1016/j.jaci.2022.04.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/28/2022] [Accepted: 04/06/2022] [Indexed: 11/26/2022]
Abstract
Mast cell activation is a key event in allergic reactions, other inflammatory states, and mast cell activation syndromes. Mast cell-stabilizing agents, mediator-targeting drugs and drugs interfering with mediator effects are often prescribed in these patients. However, the clinical efficacy of these drugs varies, depending on the numbers of involved mast cells and the underlying pathology. One straightforward approach would be to eradicate the primary target cell. However, to date, no mast cell-eradicating treatment approach has been developed for patients suffering from mast cell activation disorders. Nevertheless, recent data suggest that long-term treatment with agents that effectively inhibit KIT-function results in the virtual eradication of tissue mast cells and a sustained decrease in serum tryptase levels. In many of these patients, mast cell depletion is associated with a substantial improvement in mediator-induced symptoms. In patients with an underlying KIT D816V+ mastocytosis, such mast cell eradication requires an effective inhibitor of KIT D816V, such as avapritinib. However, the use of KIT inhibitors must be balanced against potential side effects. We here discuss mast cell-eradicating strategies in various disease models, the feasibility of this approach, available clinical data, and future prospects for the use of KIT-targeting drugs in mast cell activation disorders.
Collapse
Affiliation(s)
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria.
| | - Cem Akin
- Division of Allergy and Clinical Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Karin Hartmann
- Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Switzerland; Department of Biomedicine, University Hospital Basel and University of Basel, Switzerland
| | - Andreas Reiter
- Department of Hematology and Oncology, University Hospital Mannheim, Germany
| | - Jason Gotlib
- Stanford Cancer Institute/Stanford University School of Medicine/Stanford Cancer Institute, Stanford, CA, USA
| | - Karl Sotlar
- Institute of Pathology, Paracelsus Medical University Salzburg, Austria
| | - Wolfgang R Sperr
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria
| | - Lina Degenfeld-Schonburg
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria
| | - Dubravka Smiljkovic
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria
| | - Massimo Triggiani
- Division of Allergy and Clinical Immunology, University of Salerno, Italy
| | - Hans-Peter Horny
- Institute of Pathology, Ludwig-Maximilian-University, Munich, Germany
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Charles-Foix Hospital, AP-HP Sorbonne University, Paris, France
| | - Stephen J Galli
- Department of Pathology, Department of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, CA, USA
| | - Dean D Metcalfe
- Mast Cell Biology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, USA
| |
Collapse
|
|
17
|
Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis 2020; 100:327-332. [PMID: 32920235 PMCID: PMC7529115 DOI: 10.1016/j.ijid.2020.09.016] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 08/28/2020] [Accepted: 09/07/2020] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES One-fifth of Covid-19 patients suffer a severe course of Covid-19 infection; however, the specific causes remain unclear. Mast cells (MCs) are activated by SARS-CoV-2. Although only recently recognized, MC activation syndrome (MCAS), usually due to acquired MC clonality, is a chronic multisystem disorder with inflammatory and allergic themes, and an estimated prevalence of 17%. This paper describes a novel conjecture explaining how MCAS might cause a propensity for severe acute Covid-19 infection and chronic post-Covid-19 illnesses. METHODS Observations of Covid-19 illness in patients with/without MCAS were compared with extensive clinical experience with MCAS. RESULTS The prevalence of MCAS is similar to that of severe cases within the Covid-19-infected population. Much of Covid-19's hyperinflammation is concordant with manners of inflammation which MC activation can drive. Drugs with activity against MCs or their mediators have preliminarily been observed to be helpful in Covid-19 patients. None of the authors' treated MCAS patients with Covid-19 suffered severe infection, let alone mortality. CONCLUSIONS Hyperinflammatory cytokine storms in many severely symptomatic Covid-19 patients may be rooted in an atypical response to SARS-CoV-2 by the dysfunctional MCs of MCAS rather than a normal response by normal MCs. If proven, this theory has significant therapeutic and prognostic implications.
Collapse
Affiliation(s)
- Lawrence B Afrin
- Department of Mast Cell Studies, AIM Center for Personalized Medicine, Purchase, New York, USA.
| | | | | |
Collapse
|
|
18
|
Weiler CR, Austen KF, Akin C, Barkoff MS, Bernstein JA, Bonadonna P, Butterfield JH, Carter M, Fox CC, Maitland A, Pongdee T, Mustafa SS, Ravi A, Tobin MC, Vliagoftis H, Schwartz LB. AAAAI Mast Cell Disorders Committee Work Group Report: Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol 2019; 144:883-896. [DOI: 10.1016/j.jaci.2019.08.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/20/2019] [Accepted: 08/27/2019] [Indexed: 12/18/2022]
|
|
19
|
Abstract
PURPOSE OF REVIEW Mast cell disorders (MCDs) comprise mastocytosis and disorders referred to as mast cell activation syndrome and are caused by abnormal accumulation and/or activation of mast cells in tissues. Clinical signs and symptoms are protean; therefore, finding suitable treatment options for individual patients entails a challenge for clinicians. The purpose of this manuscript is to review the literature on the available therapeutic interventions in patients with MCD. RECENT FINDINGS Pharmacotherapy is mainly directed against the effects of mast cells and their mediators. The current recommendations are exclusively based on expert opinions due to the lack of controlled clinical trials. The targeted therapies aiming at blocking mutant KIT variants and/or downstream signaling pathways are currently being developed and may be considered in severely affected, therapy-refractory patients. SUMMARY There is currently no method for predicting the best available approach to control symptoms in individual patients with MCD. Therefore, a stepwise, individual-based approach in pharmacotherapy options appears to be most successful strategy and is recommended in all patients. The core component of the treatment in most patients is to control symptoms caused by mast cell mediator release, whereas cytoreductive therapies are mainly reserved for patients with advanced/aggressive systemic mastocytosis.
Collapse
|
|
20
|
|
|
21
|
Ribatti D. Mast cells as therapeutic target in cancer. Eur J Pharmacol 2016; 778:152-7. [PMID: 25917325 DOI: 10.1016/j.ejphar.2015.02.056] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 02/06/2015] [Accepted: 02/17/2015] [Indexed: 02/07/2023]
|
|
22
|
Gülen T, Hägglund H, Dahlén B, Nilsson G. Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease. J Intern Med 2016; 279:211-28. [PMID: 26347286 DOI: 10.1111/joim.12410] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life-threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions [i.e. urticaria pigmentosa (UP)], the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect-induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.
Collapse
Affiliation(s)
- T Gülen
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden.,Department of Medicine, Clinical Immunology and Allergy Research Unit, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.,Mastocytosis Centre Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.,Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
| | - H Hägglund
- Department of Hematology, Uppsala University Hospital, Uppsala, Sweden
| | - B Dahlén
- Department of Respiratory Medicine and Allergy, Karolinska University Hospital Huddinge, Stockholm, Sweden.,Mastocytosis Centre Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.,Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
| | - G Nilsson
- Department of Medicine, Clinical Immunology and Allergy Research Unit, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.,Mastocytosis Centre Karolinska, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.,Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
| |
Collapse
|
|
23
|
Afrin LB, Butterfield JH, Raithel M, Molderings GJ. Often seen, rarely recognized: mast cell activation disease--a guide to diagnosis and therapeutic options. Ann Med 2016; 48:190-201. [PMID: 27012973 DOI: 10.3109/07853890.2016.1161231] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Mast cell (MC) disease has long been thought to be just the rare disease of mastocytosis (in various forms, principally cutaneous and systemic), with aberrant MC mediator release at symptomatic levels due to neoplastic MC proliferation. Recent discoveries now show a new view is in order, with mastocytosis capping a metaphorical iceberg now called "MC activation disease" (MCAD, i.e. disease principally manifesting inappropriate MC activation), with the bulk of the iceberg being the recently recognized "MC activation syndrome" (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Given increasing appreciation of a great menagerie of mutations in MC regulatory elements in mastocytosis and MCAS, the great heterogeneity of MCAD's clinical presentation is unsurprising. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme. Preliminary epidemiologic investigation suggests MCAD, while often misrecognized, may be substantially prevalent, making it increasingly important that practitioners of all stripes learn how to recognize its more common forms such as MCAS. We review the diagnostically challenging presentation of MCAD (with an emphasis on MCAS) and current thoughts regarding its biology, epidemiology, natural history, diagnostic evaluation, and treatment.
Collapse
Affiliation(s)
- Lawrence B Afrin
- a Division of Hematology, Oncology, and Transplantation , University of Minnesota , Minneapolis , MN , USA
| | - Joseph H Butterfield
- b Program for the Study of Mast Cell and Eosinophil Disorders , Mayo Clinic , Rochester , MN , USA
| | - Martin Raithel
- c Department of Internal Medicine , Waldkrankenhaus St. Marien , Erlangen , Germany
| | | |
Collapse
|
|
24
|
Park CH, Kim EH, Jung DH, Chung H, Park JC, Shin SK, Lee YC, Kim H, Lee SK. Impact of periodic endoscopy on incidentally diagnosed gastric gastrointestinal stromal tumors: findings in surgically resected and confirmed lesions. Ann Surg Oncol 2015; 22:2933-2939. [PMID: 25808096 DOI: 10.1245/s10434-015-4517-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although gastric gastrointestinal stromal tumors (GISTs) are usually identified by endoscopic examinations, the diagnostic value of endoscopy has not been fully evaluated. We assessed the diagnostic performance of endoscopy for gastric GISTs according to lesion characteristics. Furthermore, the benefits of periodic endoscopy prior to diagnosis of gastric GISTs were evaluated. METHODS We reviewed patients who underwent surgery for gastric GISTs at Severance Hospital, Seoul, Korea, between January 2008 and April 2014. In addition, we administered a questionnaire to determine the usage of periodic endoscopic inspection and the period from the penultimate endoscopy to the diagnosis. RESULTS Of 174 included patients, 109 (62.4 %) showed intraluminally growing GISTs and 65 (37.4 %) showed extraluminally growing GISTs. The proportions of lesions that were initially diagnosed via endoscopy were 99.1 % for intraluminally growing GISTs and 49.2 % for extraluminally growing GISTs (P < 0.001). In patients with intraluminally growing GISTs, patients who had undergone endoscopy within 3 years prior to the diagnosis showed smaller tumor sizes (P = 0.015) and fewer tumors with ulceration (7.1 vs. 28.4 %, P = 0.021). The proportion of GISTs with a high mitotic index did not differ according to the usage of periodic endoscopy (P = 0.639). In contrast, lesion characteristics of the extraluminally growing GISTs did not differ according to whether an endoscopy was performed within 3 years prior to the diagnosis. CONCLUSIONS Endoscopic examinations had a limited role in the diagnosis of extraluminally growing GISTs. However, periodic endoscopy was associated with relatively earlier detection of growth in intraluminal gastric GISTs.
Collapse
Affiliation(s)
- Chan Hyuk Park
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Mayado A, Teodosio C, Garcia-Montero AC, Matito A, Rodriguez-Caballero A, Morgado JM, Muñiz C, Jara-Acevedo M, Álvarez-Twose I, Sanchez-Muñoz L, Matarraz S, Caldas C, Muñoz-González JI, Escribano L, Orfao A. Increased IL6 plasma levels in indolent systemic mastocytosis patients are associated with high risk of disease progression. Leukemia 2015; 30:124-30. [DOI: 10.1038/leu.2015.176] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Revised: 05/15/2015] [Accepted: 06/16/2015] [Indexed: 11/09/2022]
|
|
26
|
Marano L, Boccardi V, Marrelli D, Roviello F. Duodenal gastrointestinal stromal tumor: From clinicopathological features to surgical outcomes. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2015; 41:814-822. [PMID: 25956211 DOI: 10.1016/j.ejso.2015.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 03/01/2015] [Accepted: 04/08/2015] [Indexed: 02/07/2023]
Abstract
Duodenal gastrointestinal tumors represent an extremely rare subset of stromal tumors arising from interstitial cells of Cajal. In the last 30 years the comprehension of the pathophysiology and natural history of this previously misunderstood clinical entity, in association with developments in endoscopy, imaging technology, and immunohistochemistry has resulted in novel diagnostic and treatment approaches. This is a comprehensive review of the current data of the literature on the various aspects of the diagnosis and treatment of these tumors. The duodenum is the less commonly involved site for these tumors in the digestive tract. Endoscopy and computed tomography can usually establish the diagnosis, confirmed by immunohistochemical staining and occasionally molecular genetic analysis. Endoscopic ultrasound with fine needle aspiration has been recently found to be the gold diagnostic standard with high sensitivity and specificity rates, diagnosing GIST in up to 80% of patients. Due to the complex anatomy of the pancreatico-duodenal region optimal therapeutic strategy of duodenal GISTs are challenging. Nevertheless surgical resection with microscopically clear resection margins seems to be the only potentially curative treatment for non-metastatic primary GISTs of the duodenum. Imatinib mesylate plays a key role in the management of GISTs both as neoadjuvant therapy and in patients with recurrent and metastatic disease. Meanwhile, the advances in the comprehension of the pathophysiology and natural history of this previously misunderstood clinical entity as well as the treatment of these tumors may render feasible, in the near future, the advent of newer and more effective treatment options.
Collapse
Affiliation(s)
- L Marano
- Unit of General and Minimally Invasive Surgery, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy.
| | - V Boccardi
- Unit of General and Minimally Invasive Surgery, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy
| | - D Marrelli
- Unit of General and Minimally Invasive Surgery, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy
| | - F Roviello
- Unit of General and Minimally Invasive Surgery, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy
| |
Collapse
|
|
27
|
Kristensen T, Broesby-Olsen S, Vestergaard H, Bindslev-Jensen C, Møller MB. Targeted ultradeep next-generation sequencing as a method for KIT D816V mutation analysis in mastocytosis. Eur J Haematol 2015; 96:381-8. [PMID: 26095448 DOI: 10.1111/ejh.12601] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2015] [Indexed: 12/16/2022]
Abstract
Next-generation sequencing (NGS) is becoming increasingly used for diagnostic mutation analysis in myeloid neoplasms and may also represent a feasible technique in mastocytosis. However, detection of the KIT D816V mutation requires a highly sensitive method in most patients due to the typically low mutation levels. In this study, we established an NGS-based KIT mutation analysis and analyzed the sensitivity of D816V detection using the Ion Torrent platform. Eighty-two individual NGS analyses were included in the study. All samples were also analyzed using highly sensitive KIT D816V mutation-specific qPCR. Measurements of the background level in D816V-negative samples supported a cutoff for positivity of 0.2% in three different NGS panels. Clinical samples from patients with SM that tested positive using qPCR with a D816V allele burden >0.2% also tested positive using NGS. Samples that tested positive using qPCR with an allele burden <0.2% tested negative using NGS. We thereby demonstrate that caution should be taken when using the potentially very sensitive NGS technique for KIT D816V mutation analysis in mastocytosis, as many patients with SM have D816V mutation levels below the detection limit of NGS. A dedicated and highly sensitive KIT D816V mutation analysis therefore remains important in mastocytosis diagnostics.
Collapse
Affiliation(s)
- Thomas Kristensen
- Department of Pathology, Odense University Hospital, Odense, Denmark
| | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark
| | - Hanne Vestergaard
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | | | | | | |
Collapse
|
|
28
|
Hochhaus A, Baccarani M, Giles FJ, le Coutre PD, Müller MC, Reiter A, Santanastasio H, Leung M, Novick S, Kantarjian HM. Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study. J Cancer Res Clin Oncol 2015; 141:2047-60. [PMID: 26002753 PMCID: PMC4768228 DOI: 10.1007/s00432-015-1988-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 05/09/2015] [Indexed: 12/30/2022]
Abstract
Purpose Activating KIT mutations are part of the pathogenesis of systemic mastocytosis (SM). Nilotinib is a tyrosine kinase inhibitor that potently inhibits activated forms of KIT. This phase 2, open-label, single-arm study (CAMN107A2101; www.clinicaltrials.gov NCT00109707) evaluated nilotinib in patients with SM. Methods Patients with SM [aggressive SM (ASM), indolent SM, or other] received nilotinib 400 mg twice daily. C-findings were collected retrospectively to assess response using criteria proposed after trial initiation. Response was evaluated using improvements in laboratory findings (for all patients) and ASM response criteria (for the ASM subgroup). Results In 61 patients enrolled, the median nilotinib exposure was 232 days (range 3–1274 days) with a median follow-up of 34.7 months. In patients with ASM (n = 37), the overall response rate was 21.6 %. In the eight responders, all of whom had a KIT D816V mutation at any time, mast cell infiltration and tryptase level decreased by 70 % and 29.8 %, respectively; absolute neutrophil count increased by 94.7 %. Laboratory parameters also improved in the non-ASM subgroups. Overall survival at 24 months was 81.2 % (95 % CI 70.6–91.8 %) with median survival not yet reached. New or worsening grade 3/4 hematologic adverse events (AEs) included thrombocytopenia (10.3 %), anemia (10.0 %), and neutropenia (6.9 %). The most common grade 3/4 nonhematologic drug-related AEs were diarrhea (6.6 %) and headache (4.9 %). Eleven patients (9 with ASM, 2 with MCL) died, 10 due to progressive disease; 7 deaths occurred ≥28 days after treatment discontinuation. Conclusions Nilotinib 400 mg twice daily was effective in some patients with SM, including patients with mutated KIT D816V.
Collapse
Affiliation(s)
- Andreas Hochhaus
- Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Erlanger Allee 101, 07740, Jena, Germany.
| | | | - Francis J Giles
- Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA
| | | | - Martin C Müller
- Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
| | - Andreas Reiter
- Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany
| | | | - Mimi Leung
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Steven Novick
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | | |
Collapse
|
|
29
|
Castells MC, Hornick JL, Akin C. Anaphylaxis After Hymenoptera Sting: Is It Venom Allergy, a Clonal Disorder, or Both? THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2015; 3:350-5. [DOI: 10.1016/j.jaip.2015.03.015] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 03/28/2015] [Accepted: 03/30/2015] [Indexed: 11/28/2022]
|
|
30
|
Erbas O, Pala HG, Pala EE, Artunc Ulkumen B, Akman L, Akman T, Oltulu F, Aktug H, Yavasoglu A. Therapeutic effect of sunitinib on diabetes mellitus related ovarian injury: an experimental rat model study. Gynecol Endocrinol 2015; 31:388-91. [PMID: 25703256 DOI: 10.3109/09513590.2015.1005593] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The aim of our study is to investigate the effect of sunitinib on diabetes mellitus related-ovarian injury and fibrosis in rat models. An experimental diabetes mellitus model was created in 16 rats, and eight rats with normal blood glucose levels were included in control group (Group-1). The diabetic rats were divided into two groups:diabetic control group (water given) - Group-2 and sunitinib treatment group - Group-3. After four weeks, bilateral oophorectomy was performed and ovaries were examined histologically. The groups were compared by Student's t-test, analysis of variance (ANOVA) and Mann-Whitney's U-test. There was a significant increase in no-medication (water given) diabetic rat's ovary (Group-2) in terms of follicular degeneration, stromal degeneration, stromal fibrosis and NF-kappaB immune-expression compared with control group normal rats' ovary (Group-1) (p < 0.0001). Stromal degeneration (p = 0.04), stromal fibrosis (p = 0.01), follicular degeneration (p = 0.02), NF-kappaB immune-expression (p = 0.001) significantly decreased in sunitinib-treated diabetic rat's ovary (Group-3) when compared with no-medication (water given) diabetic rat's ovary (Group-2) (p < 0.05). When we used sunitinib in the treatment of diabetic rats, ovarian injury, fibrosis and NF-kappaB immunoexpression decreased significantly. The effects of sunitinib in rat models give hope to the improved treatment of premature ovarian failure due to diabetes mellitus in humans.
Collapse
Affiliation(s)
- Oytun Erbas
- Physiology Department, Istanbul Bilim University School of Medicine , Istanbul , Turkey
| | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Abstract
Supplemental Digital Content is Available in the Text. Some sickle cell anemia (SCA) patients suffer significantly worse phenotypes than others. Causes of such disparities are incompletely understood. Comorbid chronic inflammation likely is a factor. Recently, mast cell (MC) activation (creating an inflammatory state) was found to be a significant factor in sickle pathobiology and pain in a murine SCA model. Also, a new realm of relatively noncytoproliferative MC disease termed MC activation syndrome (MCAS) has been identified recently. MCAS has not previously been described in SCA. Some SCA patients experience pain patterns and other morbidities more congruent with MCAS than traditional SCA pathobiology (eg, vasoocclusion). Presented here are 32 poor-phenotype SCA patients who met MCAS diagnostic criteria; all improved with MCAS-targeted therapy. As hydroxyurea benefits some MCAS patients (particularly SCA-like pain), its benefit in SCA may be partly attributable to treatment of unrecognized MCAS. Further study will better characterize MCAS in SCA and identify optimal therapy.
Collapse
|
|
32
|
Barete S. Les mastocytoses. Ann Dermatol Venereol 2014; 141:698-714; quiz 697, 715. [DOI: 10.1016/j.annder.2014.08.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 07/21/2014] [Accepted: 08/29/2014] [Indexed: 01/05/2023]
|
|
33
|
Ranieri G, Marech I, Pantaleo M, Piccinno M, Roncetti M, Mutinati M, Rizzo A, Gadaleta CD, Introna M, Patruno R, Sciorsci RL. In vivo model for mastocytosis: A comparative review. Crit Rev Oncol Hematol 2014; 93:159-69. [PMID: 25465741 DOI: 10.1016/j.critrevonc.2014.10.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 10/01/2014] [Accepted: 10/22/2014] [Indexed: 12/27/2022] Open
Abstract
Human mastocytosis are heterogeneous group of neoplastic diseases characterized by a different degree of uncontrolled mast cell (MC) proliferation and activation. Interestingly, human mastocytosis share several biological and clinical features with canine mast cell disorders, so called canine mast cell tumors (CMCTs). These CMCTs are the most common spontaneous cutaneous tumors found in dogs representing a valid model to study neoplastic mast cell disorders. It has been discovered that the pathological activation of c-Kit receptor (c-KitR), expressed by MCs, has been involved in the pathogenesis of neoplastic MC disorders. In this review we have focused on human mastocytosis in terms of: (i) epidemiology and classification; (ii) pathogenesis at molecular levels; (iii) clinical presentation. In addition, we have summarized animal models useful to study neoplastic MC disorders including CMCTs and murine transgenic models. Finally, we have revised therapeutic approaches mostly common in human and canine MCTs and novel tyrosine kinase inhibitors approved for CMCTs and recently translated in human clinical trials.
Collapse
Affiliation(s)
- Girolamo Ranieri
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", Bari, Italy.
| | - Ilaria Marech
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Marianna Pantaleo
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Mariagrazia Piccinno
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Maria Roncetti
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Maddalena Mutinati
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Annalisa Rizzo
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Cosmo Damiano Gadaleta
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Marcello Introna
- Department of Pathology, Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| | - Rosa Patruno
- Department of Prevention and Animal Health, ASL BAT, Barletta, Italy
| | - Raffaele Luigi Sciorsci
- Department of Emergency and Organ Transplantation (D.E.T.O.), Veterinary Medical School, Università "Aldo Moro", Bari, Italy
| |
Collapse
|
|
34
|
Iorio N, Sawaya RA, Friedenberg FK. Review article: the biology, diagnosis and management of gastrointestinal stromal tumours. Aliment Pharmacol Ther 2014; 39:1376-86. [PMID: 24749828 DOI: 10.1111/apt.12761] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2014] [Revised: 03/19/2014] [Accepted: 03/27/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract with an increasing incidence. AIMS To review the biology, diagnosis and treatment of gastrointestinal stromal tumours. METHODS A PubMed search using the phrases 'Gastrointestinal stromal tumor', 'imatinib', 'c-kit'. RESULTS The diagnosis of GIST is established by histology supplemented by the immunohistochemical marker CD117, which is positive in 95% of cases. The most common site of the tumour is the stomach. Most GIST are benign with 20-30% malignant. Five-year survival for malignant GIST ranges between 35% and 65% and depends primarily on tumour size, mitotic index and location. The malignant behaviour of GIST is best assessed by invasion of adjacent structures and distant metastases. The gold standard for treatment is surgical resection. Imatinib, a tyrosine kinase inhibitor, is the primary therapy for unresectable, recurrent or metastatic disease. CONCLUSIONS Gastrointestinal stromal tumours are rare tumours of the gastrointestinal tract and they vary in presentation. When surgical resection is not achievable, imatinib is the treatment of choice.
Collapse
Affiliation(s)
- N Iorio
- Department of Medicine, Temple University Hospital, Philadelphia, PA, USA
| | | | | |
Collapse
|
|
35
|
Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller MB, Broesby-Olsen S. Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol 2014; 89:493-8. [PMID: 24443360 DOI: 10.1002/ajh.23672] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 01/11/2014] [Accepted: 01/14/2014] [Indexed: 01/08/2023]
Abstract
The recent progress in sensitive KIT D816V mutation analysis suggests that mutation analysis of peripheral blood (PB) represents a promising diagnostic test in mastocytosis. However, there is a need for systematic assessment of the analytical sensitivity and specificity of the approach in order to establish its value in clinical use. We therefore evaluated sensitive KIT D816V mutation analysis of PB as a diagnostic test in an entire case-series of adults with mastocytosis. We demonstrate for the first time that by using a sufficiently sensitive KIT D816V mutation analysis, it is possible to detect the mutation in PB in nearly all adult mastocytosis patients. The mutation was detected in PB in 78 of 83 systemic mastocytosis (94%) and 3 of 4 cutaneous mastocytosis patients (75%). The test was 100% specific as determined by analysis of clinically relevant control patients who all tested negative. Mutation analysis of PB was significantly more sensitive than serum tryptase >20 ng/mL. Of 27 patients with low tryptase, 26 tested mutation positive (96%). The test is furthermore readily available and we consider the results to serve as a foundation of experimental evidence to support the inclusion of the test in diagnostic algorithms and clinical practice in mastocytosis.
Collapse
Affiliation(s)
| | - Hanne Vestergaard
- Department of Hematology; Odense University Hospital; Odense Denmark
| | | | | | - Sigurd Broesby-Olsen
- Department of Dermatology and Allergy Centre; Odense University Hospital; Odense Denmark
| | | |
Collapse
|
|
36
|
Akin C, Valent P. Diagnostic Criteria and Classification of Mastocytosis in 2014. Immunol Allergy Clin North Am 2014; 34:207-18. [DOI: 10.1016/j.iac.2014.02.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
37
|
Abstract
Eosinophils and mast cells coexist in clonal and nonclonal disorders. The interplay between these cells is complex and not fully understood. Discussed are both allergic/nonclonal disorders in which both cell types are increased in number are likely to play a role in pathogenesis and clonal disorders in which both cell types are affected and play key roles in pathogenesis. Finally, some treatment options, keeping both disorders in mind, are discussed. Future directions in thinking about these disorders are also briefly explored.
Collapse
Affiliation(s)
- Anna Kovalszki
- Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
| | - Peter F Weller
- Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue CLS943, Boston, MA 02215, USA; Division of Infectious Diseases, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue CLS943, Boston, MA 02215, USA
| |
Collapse
|
|
38
|
Shamloo A, Manchandia M, Ferreira M, Mani M, Nguyen C, Jahn T, Weinberg K, Heilshorn S. Complex chemoattractive and chemorepellent Kit signals revealed by direct imaging of murine mast cells in microfluidic gradient chambers. Integr Biol (Camb) 2014; 5:1076-85. [PMID: 23835699 DOI: 10.1039/c3ib40025e] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Besides its cooperating effects on stem cell proliferation and survival, Kit ligand (KL) is a potent chemotactic protein. While transwell assays permit studies of the frequency of migrating cells, the lack of direct visualization precludes dynamic chemotaxis studies. In response, we utilize microfluidic chambers that enable direct observation of murine bone marrow-derived mast cells (BMMC) within stable KL gradients. Using this system, individual Kit+ BMMC were quantitatively analyzed for migration speed and directionality during KL-induced chemotaxis. Our results indicated a minimum activating threshold of ~3 ng ml(-1) for chemoattraction. Analysis of cells at KL concentrations below 3 ng ml(-1) revealed a paradoxical chemorepulsion, which has not been described previously. Unlike chemoattraction, which occurred continuously after an initial time lag, chemorepulsion occurred only during the first 90 minutes of observation. Both chemoattraction and chemorepulsion required the action of G-protein coupled receptors (GPCR), as treatment with pertussis toxin abrogated directed migration. These results differ from previous studies of GPCR-mediated chemotaxis, where chemorepulsion occurred at high ligand concentrations. These data indicate that Kit-mediated chemotaxis is more complex than previously understood, with the involvement of GPCRs in addition to the Kit receptor tyrosine kinase and the presence of both chemoattractive and chemorepellent phases.
Collapse
Affiliation(s)
- Amir Shamloo
- Department of Mechanical Engineering, Stanford University, Stanford, CA 94305-4045, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
Collapse
|
|
40
|
Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
Collapse
|
|
41
|
Erben P, Schwaab J, Metzgeroth G, Horny HP, Jawhar M, Sotlar K, Fabarius A, Teichmann M, Schneider S, Ernst T, Müller MC, Giehl M, Marx A, Hartmann K, Hochhaus A, Hofmann WK, Cross NCP, Reiter A. The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol 2013; 93:81-8. [PMID: 24281161 DOI: 10.1007/s00277-013-1964-1] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 11/11/2013] [Indexed: 11/29/2022]
Abstract
The activating KIT D816V mutation plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). For improved and reliable identification of KIT D816V, we have developed an allele-specific quantitative real-time PCR (RQ-PCR) with an enhanced sensitivity of 0.01-0.1 %, which was superior to denaturing high-performance liquid chromatography (0.5-1 %) or conventional sequencing (10-20 %). Overall, KIT D816 mutations were identified in 146/147 (99 %) of patients (D816V, n = 142; D816H, n = 2; D816Y, n = 2) with SM, including indolent SM (ISM, n = 63, 43 %), smoldering SM (n = 8, 5 %), SM with associated hematological non-mast cell lineage disease (SM-AHNMD, n = 16, 11 %), and aggressive SM/mast cell leukemia ± AHNMD (ASM/MCL, n = 60, 41 %). If positive in BM, the KIT D816V mutation was found in PB of all patients with advanced SM (SM-AHNMD, ASM, and MCL) and in 46 % (23/50) of patients with ISM. There was a strong correlation between the KIT D816V expressed allele burden (KIT D816V EAB) with results obtained from DNA by genomic allele-specific PCR and also with disease activity (e.g., serum tryptase level), disease subtype (e.g., indolent vs. advanced SM) and survival. In terms of monitoring of residual disease, qualitative and quantitative assessment of KIT D816V and KIT D816V EAB was successfully used for sequential analysis after chemotherapy or allogeneic stem cell transplantation. We therefore conclude that RQ-PCR assays for KIT D816V are useful complimentary tools for diagnosis, disease monitoring, and evaluation of prognosis in patients with SM.
Collapse
Affiliation(s)
- Philipp Erben
- III. Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Afrin LB. Utility of hydroxyurea in mast cell activation syndrome. Exp Hematol Oncol 2013; 2:28. [PMID: 24192267 PMCID: PMC3851743 DOI: 10.1186/2162-3619-2-28] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Accepted: 10/06/2013] [Indexed: 02/07/2023] Open
Abstract
Mast cell activation syndrome (MCAS) is a relatively recently recognized cause of chronic multisystem polymorbidity of a generally inflammatory theme. Patients with MCAS often report migratory soft tissue and/or bone pain which frequently responds poorly to typical (narcotic and non-narcotic) analgesics as well as atypical analgesics such as antidepressants and anticonvulsants. Hydroxyurea (HU) is an oral ribonucleotide reductase inhibitor commonly used in the treatment of chronic myeloproliferative neoplasms and sickle cell anemia. HU has been used to treat systemic mastocytosis, sometimes effecting improvement in MC activation symptoms but not tumor burden, suggesting potential utility of the drug in MCAS, too. Reported here are five cases of successful use of relatively low-dose HU in MCAS to reduce symptoms including previously refractory soft tissue and/or bone pain. HU may be useful in treating mediator symptoms in MCAS, but further study is needed to define optimal dosing strategies and patient subpopulations most likely to benefit.
Collapse
Affiliation(s)
- Lawrence B Afrin
- Division of Hematology/Oncology, Medical University of South Carolina, Charleston, South Carolina, USA.
| |
Collapse
|
|
43
|
Pinto-Lopes P, Fonseca FA, Silva R, Hafe PV, Fonseca E. Indolent systemic mastocytosis limited to the bone: a case report and review of the literature. SAO PAULO MED J 2013; 131:198-204. [PMID: 23903270 PMCID: PMC10852104 DOI: 10.1590/1516-3180.2013.1313460] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 01/29/2012] [Accepted: 09/21/2012] [Indexed: 01/08/2023] Open
Abstract
CONTEXT Systemic mastocytosis is defined as a clonal disorder of mast cells and their precursor cells and is currently classified as a myeloproliferative neoplasm. Its clinical course has a wide spectrum, ranging from indolent disease, with normal life expectancy, to highly aggressive disease, associated with multisystemic involvement and poor overall survival. The aim of this study was to report a case of indolent systemic mastocytosis, focusing on the diagnostic challenges, with a review of the literature. CASE REPORT A 79-year-old Caucasian woman with osteoporosis was evaluated at the Emergency Department because of complaints of low back pain. Before this, she had consulted an orthopedist and had undergone some imaging examinations, namely a bone scan that revealed a "superscan" pattern. Due to her pain complaints and these test results, the patient was admitted to the Department of Internal Medicine. After undergoing several analytical tests and some additional imaging examinations to rule out some important differential diagnoses, she then underwent bone marrow biopsy, which made it possible to identify indolent systemic mastocytosis. CONCLUSION Systemic mastocytosis is a rare entity that is difficult to diagnose. Its symptoms are often unspecific and frequently ignored. Skeletal changes may be the first and only manifestation of the disease and in some cases, like this one, the diagnosis is made only after histological examination. The key point for the diagnosis is to contemplate the possibility of systemic mastocytosis.
Collapse
|
|
44
|
|
|
45
|
Lewis A, Wan J, Baothman B, Monk PN, Suvarna SK, Peachell PT. Heterogeneity in the responses of human lung mast cells to stem cell factor. Clin Exp Allergy 2012; 43:50-9. [DOI: 10.1111/cea.12045] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 09/24/2012] [Accepted: 10/12/2012] [Indexed: 11/29/2022]
Affiliation(s)
- A. Lewis
- Academic Unit of Respiratory Medicine; The Medical School; University of Sheffield; Beech Hill Road; Sheffield; S10 2RX; UK
| | - J. Wan
- Academic Unit of Respiratory Medicine; The Medical School; University of Sheffield; Beech Hill Road; Sheffield; S10 2RX; UK
| | - B. Baothman
- Academic Unit of Respiratory Medicine; The Medical School; University of Sheffield; Beech Hill Road; Sheffield; S10 2RX; UK
| | - P. N. Monk
- Department of Infection and Immunity; The Medical School; University of Sheffield; Beech Hill Road; Sheffield; S10 2RX; UK
| | - S. K. Suvarna
- Department of Histopathology; Northern General Hospital; Herries Road; Sheffield; S5 7AU; UK
| | - P. T. Peachell
- Academic Unit of Respiratory Medicine; The Medical School; University of Sheffield; Beech Hill Road; Sheffield; S10 2RX; UK
| |
Collapse
|
|
46
|
Vaali K, Lappalainen J, Lin AH, Mäyränpää MI, Kovanen PT, Berstad A, Eklund KK. Imatinib mesylate alleviates diarrhea in a mouse model of intestinal allergy. Neurogastroenterol Motil 2012; 24:e325-35. [PMID: 22709239 DOI: 10.1111/j.1365-2982.2012.01941.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND When sensitized epicutaneously and challenged orally with ovalbumin, Balb/c mice develop allergen-induced diarrhea. As mast cells play important roles in diarrhea, we studied whether allergic diarrhea could be alleviated with imatinib mesylate. METHODS Balb/c mice were sensitized and challenged with ovalbumin and treated orally with imatinib. Cytokine mRNA expressions were determined with quantitative RT-PCR and numbers of small intestinal mast cells determined by staining for chloroacetate esterase and mucosal mast cell protease-1. Immunofluorescence staining was used to assess the intestinal CCL1 expression. KEY RESULTS Ovalbumin-sensitized and challenged Balb/c mice developed diarrhea, which was associated with increased number of mast cells and expression of interleukin (IL)-4 and -13, and chemokines CCL1 and CCL17 in the small intestine. Treatment with imatinib reduced the incidence of diarrhea, inhibited the development of mastocytosis and jejunal mRNA expression of IL-13, CCL1, CCL17 and CCL22. Mast cell-deficient W/W(-V) mice, and surprisingly, also their mast cell-competent control (+/+) littermates failed to develop diarrhea as a response to ovalbumin. This strain-dependent difference was associated with the inability of +/+ and W/W(-V) mice to increase the number of intestinal mast cells and expression of IL-4, IL-13, CCL1 and CCL17 after ovalbumin challenge. CONCLUSIONS & INFERENCES Development of allergic diarrhea is associated with the ability of mice to develop intestinal mastocytosis. Imatinib inhibited the development of intestinal mastocytosis, reduced the incidence of diarrhea, and reduced the expression of IL-13, CCL1, and CCL17. Targeting intestinal mast cells could be a feasible approach to treat allergic diarrhea.
Collapse
Affiliation(s)
- K Vaali
- Institute of Medicine, University of Bergen, Norway.
| | | | | | | | | | | | | |
Collapse
|
|
47
|
|
|
48
|
Afrin LB. Sclerosing mediastinitis and mast cell activation syndrome. Pathol Res Pract 2012; 208:181-5. [PMID: 22296862 DOI: 10.1016/j.prp.2011.12.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Revised: 11/27/2011] [Accepted: 12/27/2011] [Indexed: 01/30/2023]
Abstract
BACKGROUND Sclerosing mediastinitis (ScM) is a rare, potentially life-threatening disorder, idiopathic in roughly half the cases. Systemic symptoms not attributable to sclerosis often appear in idiopathic ScM. Mast cell activation disease (MCAD) is a potential cause of these symptoms and also can cause sclerosis. ScM has not previously been associated with MCAD. Presented here are the first two cases of ScM associated with MCAD, specifically mast cell activation syndrome (MCAS). CASE 1: A 58-year-old chronically polymorbid woman developed ScM following matched sibling allogeneic stem cell transplantation. Eight years later MCAS, likely underlying most of her chronic issues, was identified. CASE 2: A 30-year-old chronically polymorbid woman presented with superior vena cava syndrome and was diagnosed with ScM. On further evaluation, MCAS was identified. Treatment promptly effected symptomatic improvement; sclerosis has been stable. Non-compliance yielded symptomatic relapse; restored compliance re-achieved symptomatic remission. CONCLUSIONS Different MCAS presentations reflect elaboration of different mediators, some of which can induce inflammation and fibrosis. Thus, MCAS may have directly and/or indirectly driven ScM in these patients. MCAS should be considered in ScM presenting with comorbidities better explained by mast cell mediator release.
Collapse
Affiliation(s)
- Lawrence B Afrin
- Division of Hematology/Oncology, Medical University of South Carolina, Charleston, SC, USA.
| |
Collapse
|
|
49
|
Rodriguez S, Fadlalla K, Graham T, Tameru B, Fermin CD, Samuel T. Immunohistochemical evaluation of AKT protein activation in canine mast cell tumours. J Comp Pathol 2012; 147:171-6. [PMID: 22289273 DOI: 10.1016/j.jcpa.2011.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2011] [Revised: 10/28/2011] [Accepted: 12/02/2011] [Indexed: 02/04/2023]
Abstract
The pathogenesis of canine mast cell tumour (MCT) remains unknown. Moreover, therapeutic options are limited and resistance to targeted drugs and recurrences are common, necessitating the identification of additional cellular targets for therapy. In this study we investigated the expression of phosphorylated AKT protein in 25 archival canine MCT samples by immunohistochemistry and examined the correlation between the immunohistochemical scores and histopathological tumour grades. AKT protein was detected in all of the samples and 24 of the 25 samples expressed the phosphorylated form of the protein, albeit with variable intensity. However, when the immunohistochemical scores of weak, intermediate and strong labelling were compared with the histopathological grades I to III, there was no strong correlation. This study suggests that canine MCT cells have activated AKT and indicates the need for further research on the role of the AKT protein and the possibility of targeting the AKT signalling pathway in MCTs.
Collapse
Affiliation(s)
- S Rodriguez
- Department of Pathobiology, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088, USA
| | | | | | | | | | | |
Collapse
|
|
50
|
Yamaki K, Yoshino S. Tyrosine kinase inhibitor sunitinib relieves systemic and oral antigen-induced anaphylaxes in mice. Allergy 2012; 67:114-22. [PMID: 21933194 DOI: 10.1111/j.1398-9995.2011.02717.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Systemic and oral antigen-induced anaphylaxes are mediated by immunoglobulin (Ig) E and mast cells, but there is no satisfactory treatment for the life-threatening allergic reaction. We investigated the potential of the multitargeted receptor tyrosine kinase inhibitor sunitinib to relieve anaphylactic reactions in food allergy and systemic anaphylaxis. METHODS Efficacy of oral sunitinib on oral and parenteral antigen-induced anaphylaxes in Balb/c mice was evaluated. IgE-dependent degranulation and growth of rat basophilic leukemia RBL2H3 and bone marrow-derived mast cells (BMMCs) in response to sunitinib were investigated. RESULTS Daily administration of sunitinib throughout antigen challenges prevented oral antigen-induced anaphylaxis including diarrhea, anaphylactic symptoms, and hypothermia. The mouse mast cell protease (MMCP)-1 concentration in serum and mast cell number in intestinal tissue after challenge were also decreased by the treatment. Spleen cells from sunitinib-treated mice contained smaller numbers of antigen-specific IgG-producing cells and secreted lower amounts of both Th1 and Th2 cytokines than those of the control mice, whereas the levels of antigen-specific antibodies in serum were not decreased. The reactions and MMCP-1 release in oral antigen-induced anaphylaxis and passive systemic anaphylaxis were attenuated even by a single predose of sunitinib. Degranulation and growth of RBL2H3 cells and BMMCs were greatly reduced by sunitinib. CONCLUSION These results suggested that sunitinib relieves systemic and oral antigen-induced anaphylaxes by the prevention of mast cell activation and hyperplasia in intestinal tissue directly and indirectly through an immunosuppressive effect. Sunitinib and its related kinase inhibitors might be potential drugs for the treatment of food allergy and systemic anaphylaxis.
Collapse
Affiliation(s)
- K Yamaki
- Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe, Hyogo, Japan.
| | | |
Collapse
|