Zhang HB, Jiang HH, Deng JC, Zhang N. Bone marrow niche adaptation, leukemic stem cell persistence, and therapeutic resistance in FLT3-mutated leukemia. World J Stem Cells 2026; 18(7): 119893 [DOI: 10.4252/wjsc.119893]
Corresponding Author of This Article
Nan Zhang, Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, No. 288 Tianwen Avenue, Nan’an District, Chongqing 400010, China. zhangnan@hospital.cqmu.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
review-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Stem Cells. Jul 26, 2026; 18(7): 119893 Published online Jul 26, 2026. doi: 10.4252/wjsc.119893
Bone marrow niche adaptation, leukemic stem cell persistence, and therapeutic resistance in FLT3-mutated leukemia
Huai-Bin Zhang, Hui-Hui Jiang, Jian-Chuan Deng, Nan Zhang
Huai-Bin Zhang, Hui-Hui Jiang, Jian-Chuan Deng, Nan Zhang, Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
Co-first authors: Huai-Bin Zhang and Hui-Hui Jiang.
Co-corresponding authors: Jian-Chuan Deng and Nan Zhang.
Author contributions: Zhang HB and Jiang HH contributed equally to this manuscript and are co-first authors of this manuscript. Zhang HB collected and reviewed the literature and drafted the manuscript; Jiang HH assisted with literature collection and manuscript revision; Deng JC and Zhang N contributed equally as co-corresponding authors. Deng JC conceptualized the study and revised the manuscript; Zhang N designed the study and supervised the manuscript preparation. All authors read and approved the final version of the manuscript.
AI contribution statement: No AI tools were used for literature retrieval, data interpretation, or scientific content generation in this manuscript.
Supported by the National Natural Science Foundation of China, No. 82500204; and the Natural Science Foundation of Chongqing, No. CSTB2025NSCQ-GPX1181.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Nan Zhang, Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, No. 288 Tianwen Avenue, Nan’an District, Chongqing 400010, China. zhangnan@hospital.cqmu.edu.cn
Received: February 10, 2026 Revised: March 9, 2026 Accepted: June 9, 2026 Published online: July 26, 2026 Processing time: 165 Days and 4.2 Hours
Abstract
FLT3 mutations, especially FLT3-internal tandem duplication and FLT3-tyrosine kinase domain mutations, are among the most common genetic lesions in acute myeloid leukemia (AML) and are closely associated with aggressive disease biology, early relapse, and poor survival. Although FLT3 inhibitors have improved outcomes in both newly diagnosed and relapsed/refractory AML, durable remission remains limited by adaptive resistance and the persistence of leukemia stem cells. Increasing evidence indicates that treatment failure in FLT3-mutated AML is not determined solely by secondary kinase mutations, but also by dynamic interactions between leukemic cells and the bone marrow microenvironment (BMM). The BMM provides structural support, soluble mediators, metabolic substrates, and immune protection, thereby preserving a therapy-tolerant leukemic reservoir. This review summarizes the molecular features of FLT3 mutations, the bidirectional crosstalk between FLT3-mutated leukemia cells and the BMM, the formation of leukemia stem cell-supportive niches, and the principal mechanisms of microenvironment-mediated resistance, including adhesion signaling, chemokine retention, bypass pathway activation, autophagy, metabolic adaptation, and immune evasion. It also discusses emerging combination strategies aimed at cotargeting FLT3 signaling, the supportive niche, and stem-cell-specific vulnerabilities.
Core Tip: FLT3-mutated leukemia remains clinically challenging because therapeutic resistance is driven not only by intrinsic oncogenic signaling, but also by adaptive interactions with the bone marrow microenvironment. This review highlights how stromal protection, chemokine-mediated retention, hypoxic support, metabolic rewiring, immune evasion, and leukemia stem cell persistence collectively promote treatment failure and relapse. It also summarizes current and emerging therapeutic strategies aimed at cotargeting FLT3 signaling, the supportive niche, and stem cell-related vulnerabilities.
