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Cell Stem Cell. 2019 Jan 3;24(1):153-165.e7. doi: 10.1016/j.stem.2018.10.016. Epub 2018 Nov 21.

IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation.

Author information

1
Molecular Pharmacology Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
7
Molecular Pharmacology Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: kharasm@mskcc.org.

Abstract

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.

KEYWORDS:

C/EBP; HOXA9; IKZF2; leukemic stem cells

PMID:
30472158
DOI:
10.1016/j.stem.2018.10.016

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