Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability

Nat Commun. 2022 Nov 21;13(1):7124. doi: 10.1038/s41467-022-34653-3.


The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as evidenced by mass cytometry analysis of B-lineage cells derived from ETV6-RUNX1 knock-in human pluripotent stem cells. In frank leukemia, knockdown of RUNX1 or its co-factor CBFβ results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBFβ-inhibitor. Strikingly, we show that RUNX1 addiction extends to other genetic subtypes of pediatric B-ALL and also adult disease. Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results suggest that chemical intervention in the RUNX1 program may provide a therapeutic opportunity in ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B-Lymphocytes
  • Child
  • Core Binding Factor Alpha 2 Subunit* / genetics
  • Core Binding Factors
  • Gene Fusion
  • Humans
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / therapy


  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factors