IKZF2 drives leukemia stem cell self-renewal and inhibits myeloid differentiation Journal Article

Authors: Park, S. M.; Cho, H.; Thornton, A. M.; Barlowe, T. S.; Chou, T.; Chhangawala, S.; Fairchild, L.; Taggart, J.; Chow, A.; Schurer, A.; Gruet, A.; Witkin, M. D.; Kim, J. H.; Shevach, E. M.; Krivtsov, A.; Armstrong, S. A.; Leslie, C.; Kharas, M. G.
Article Title: IKZF2 drives leukemia stem cell self-renewal and inhibits myeloid differentiation
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. © 2018 Elsevier Inc. Park et al. find that IKZF2 regulates chromatin accessibility of self-renewal and differentiation genes in leukemic stem cells. Depletion of IKZF2 has preferential effect in leukemic stem cells compared to normal hematopoietic stem cells, providing a new strategy for targeting leukemic stem cells. © 2018 Elsevier Inc.
Keywords: leukemic stem cells; hoxa9; c/ebp; ikzf2
Journal Title: Cell Stem Cell
Volume: 24
Issue: 1
ISSN: 1934-5909
Publisher: Cell Press  
Date Published: 2019-01-03
Start Page: 153
End Page: 165.e7
Language: English
DOI: 10.1016/j.stem.2018.10.016
PUBMED: 30472158
PROVIDER: scopus
PMCID: PMC6602096
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Jun Hyun Kim
    9 Kim
  2. Christina Leslie
    159 Leslie
  3. Michael Kharas
    73 Kharas
  4. Sun Mi Park
    18 Park
  5. Trevor Stephen Barlowe
    12 Barlowe
  6. James Christopher Taggart
    14 Taggart
  7. Matthew David Witkin
    14 Witkin
  8. Arthur W Chow
    15 Chow
  9. Hyunwoo   Cho
    6 Cho
  10. Timothy Chou
    13 Chou
  11. Antoine Gruet
    4 Gruet
  12. Alexandra Schurer
    11 Schurer