期刊
CELL STEM CELL
卷 24, 期 1, 页码 153-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2018.10.016
关键词
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资金
- NIH National Institute of Diabetes Digestive and Kidney Diseases Career Development Award
- NIDDK NIH [R01-DK101989-01A1]
- NCI [1R01CA193842-01]
- NHLBI [R01-HL135564, 1R01CA225231-01]
- Kimmel Scholar Award
- V-Scholar Award
- Geoffrey Beene Award
- Leukemia Lymphoma Society Career Development Award
- Starr Cancer Consortium
- Alex's Lemonade Stand A Award
- NIH/NCI Cancer Support Core Grant [P30 CA08748]
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, USA
- NIH [CA176745, CA066996]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000959] Funding Source: NIH RePORTER
Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self-renewal gene expression program and inhibits a C/EBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia.
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