EVI1 drives leukemogenesis through aberrant ERG activation

Johannes Schmoellerl, Inês A.M. Barbosa, Martina Minnich, Florian Andersch, Leonie Smeenk, Marije Havermans, Thomas Eder, Tobias Neumann, Julian Jude, Michaela Fellner, Anja Ebert, Monika Steininger, Ruud Delwel, Florian Grebien*, Johannes Zuber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Chromosomal rearrangements involving the MDS1 and EVI1 complex locus (MECOM) on chromosome 3q26 define an aggressive subtype of acute myeloid leukemia (AML) that is associated with chemotherapy resistance and dismal prognosis. Established treatment regimens commonly fail in these patients, therefore, there is an urgent need for new therapeutic concepts that will require a better understanding of the molecular and cellular functions of the ecotropic viral integration site 1 (EVI1) oncogene. To characterize gene regulatory functions of EVI1 and associated dependencies in AML, we developed experimentally tractable human and murine disease models, investigated the transcriptional consequences of EVI1 withdrawal in vitro and in vivo, and performed the first genome-wide CRISPR screens in EVI1-dependent AML. By integrating conserved transcriptional targets with genetic dependency data, we identified and characterized the ETS transcription factor ERG as a direct transcriptional target of EVI1 that is aberrantly expressed and selectively required in both human and murine EVI1–driven AML. EVI1 controls the expression of ERG and occupies a conserved intragenic enhancer region in AML cell lines and samples from patients with primary AML. Suppression of ERG induces terminal differentiation of EVI1-driven AML cells, whereas ectopic expression of ERG abrogates their dependence on EVI1, indicating that the major oncogenic functions of EVI1 are mediated through aberrant transcriptional activation of ERG. Interfering with this regulatory axis may provide entry points for the development of rational targeted therapies.

Original languageEnglish
JournalBlood
DOIs
Publication statusAccepted/In press - 14 Sep 2022

Bibliographical note

Funding Information:
This work was supported by starting grants from the European Research Council to ( 336860 ) (J.Z.) and to ( 636855 ) (F.G.), the Austrian Science Fund (SFB grant F4710 ) (J.Z.), a fellowship from the Daniel den Hoed, Erasmus Medical Center Foundation (L.S.), and the Koningin Wilhelmina Fonds grant from the Dutch Cancer Society (R.D.). J.S. is a recipient of a Doctoral Fellowship Programme of the Austrian Academy of Sciences. Research at the IMP is generously supported by Boehringer Ingelheim and the Austrian Research Promotion Agency (headquarter grant FFG-852936 ).

Publisher Copyright: © 2022 The American Society of Hematology

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