期刊
EXPERIMENTAL HEMATOLOGY
卷 110, 期 -, 页码 34-38出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2022.03.005
关键词
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资金
- American Society of Hematology
- Elsa U. Pardee Foundation
- National Institutes of Health [P30 CA125123-12, R01 CA249867, CA125123, RR024574, DK56338]
- Cancer Prevention and Research Institute of Texas [P30 CA125123-12]
- Dan L. Duncan Comprehensive Cancer Center
- John S. Dunn Gulf Coast Consortium for Chemical Genomics
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- CPRIT Core Facil-ity Support Award [R01 CA249867]
- Fabio Stossi of the Integrated Microscopy Core at Baylor College of Medicine
- Integrated Microscopy Core at Baylor College of Medicine
- CPRIT [RP170074]
- [CPRIT-RP180672]
- [RP170719]
Children with Down syndrome are more likely to develop B-cell acute lymphoblastic leukemia, and CRLF2 overexpression plays a crucial role in this process. CRLF2 overexpression reduces B-cell differentiation and enhances E2F signaling, potentially providing a target for therapy.
Children with Down syndrome (DS) are 10-fold more likely to develop B-cell acute lymphoblastic leukemia (B-ALL), with a higher frequency of rearrangements resulting in overexpression of cytokine receptor-like fac-tor 2 (CRLF2). Here, we investigated the impact of CRLF2 overexpression on B-cell progenitor proliferation, immunophenotype, and gene expression profile in the Dp(16)1Yey (Dp16) mouse model of DS compared with wild-type (WT) mice. CRLF2 overexpression enhanced immature B-lymphoid colony development and increased the proportion of less differentiated pre-pro-B cells, with a greater effect in Dp16 versus WT. In CRLF2-rearranged (CRLF2-R) B-ALL patient samples, cells with higher CRLF2 expression exhibited a less differentiated B-cell immunophenotype. CRLF2 overexpression resulted in a gene expression signature associated with E2F signaling both in Dp16 B-progenitors and in DS-ALL patient samples, and PI3K/mTOR and pan-CDK inhibitors, which reduce E2F-mediated signaling, exhibited cytotoxicity in CRLF2-R B-ALL cell lines and patient samples. CRLF2 overexpression alone in Dp16 stem and progenitor cells did not result in leukemic transformation in recipient mice. Thus, CRLF2 overexpression results in reduced B-cell differen-tiation and enhanced E2F signaling in Dp16 B-progenitor cells and DS-ALL patient samples. These findings suggest a functional basis for the high frequency of CRLF2-R in DS-ALL as well as a potential therapeutically targetable pathway.(c) 2022 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
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