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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Wray, Jason P 
Deltcheva, Elitza M 
Richardson, Simon Е  ORCID logo  https://orcid.org/0000-0003-4343-4784
Chhetri, Jyoti Bikram 

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.

Description

Funder: Blood Cancer UK/Grant Number 16001

Keywords

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

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (203151/Z/16/Z)