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

Jason P. Wray, Elitza M. Deltcheva, Charlotta Boiers, Simon Richardson, Jyoti Bikram Chhetri, John Brown, Sladjana Gagrica, Yanping Guo, Anuradha Illendula, Joost H.A. Martens, Hendrik G. Stunnenberg, John H. Bushweller, Rachael Nimmo, Tariq Enver

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number7124
Pages (from-to)7124
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 21 Nov 2022
Externally publishedYes

Keywords

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

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