期刊
BLOOD
卷 125, 期 19, 页码 2968-2973出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-05-576421
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资金
- National Institutes of Health, National Institute of Allergy and Infectious Diseases [1R21AI103652-01A1]
- American Cancer Society Research Scholar grant
- University of Texas MD Anderson Cancer Center Institutional Research grant
- Leukemia SPORE Developmental Research Award
- MD Anderson Cancer Center Support grant from the National Institutes of Health, National Cancer Institute [CA016672]
Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL.
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