3070 – IL-3 RESCUES PROLIFERATIVE DEFECTS IN INFLAMMATION-SENSITIVE RUNX1 DEFICIENT HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS

Abstract

Although loss-of-function RUNX1 mutations are commonly found in hematopoietic malignancies, how RUNX1 functions during hematopoietic and leukemic development is unclear. Using a CRISPR/AAV6 system to target the RUNX1 locus in human CD34+ hematopoietic stem and progenitor cells (HSPCs), we show that RUNX1 deficiency causes monocytic skew at the expense of erythro-megakaryocytic potential and stem cell activity, including a severe in vivo stem cell competitive defect. RNA-seq and ATAC-seq review that these effects are mediated by broad upregulation of PU.1 and NFKB transcriptional programs; downregulation of GATA1- and TAL1-dependent erythro-megakaryocytic differentiation; and downregulation of cell cycle programs mediated by MYC and E2F. Treatment with IL-3 rescues RUNX1-deficient cell proliferative and stem cell defects. Together, these results show that RUNX1 controls transcription factor activity and cytokine signaling, and loss of RUNX1 causes monocytic skewing and hypersensitivity to IL-3-dependent expansion. We are currently studying how the IL-3 selects for inflammation-sensitive RUNX1 deficient cells and whether targeting IL-3 signaling may be a viable therapeutic in the prevention or treatment of RUNX1 mutant malignancies.