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

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. [Display omitted] •IKZF2 is a chromatin remodeler, highly expressed in leukemic stem cells•IKZF2 maintains self-renewal and inhibits differentiation in leukemic stem cells•CUT&RUN assay shows that IKZF2 binds to IKZF2 motifs adjacent to HOXA9 and CEBPD/E motifs•IKZF2 regulates accessibility of HOXA9 and CEBPD/E motifs, modulating gene expression 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.