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 language | English |
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Pages (from-to) | 453-466 |
Number of pages | 14 |
Journal | Blood |
Volume | 141 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2 Feb 2023 |
Bibliographical note
Funding Information:The authors thank all colleagues from the Zuber and Grebien groups for scientific discussions, Gerald Schmauss, Marietta Weninger, and Mario Nezhyba for expert fluorescence-activated cell sorting, and Pawel Pasierbek for imaging advice. The authors are grateful to the Molecular Biology Services as well as to the animal care takers at Institute of Molecular Pathology (IMP)/Institute of Molecular Biotechnology of the Austrian Academy of Sciences, and to Andreas Sommer and his team at the Vienna BioCenter Core Facilities (https://www.vbcf.ac.at) for deep sequencing services. The authors also thank Yosuke Masamoto and Mineo Kurokawa for scientific discussions and for sharing unpublished data and manuscript drafts. 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). Contribution: J.S. I.A.M.B. F.G. and J.Z. conceptualized the study; J.S. I.A.M.B. F.A. J.J. and J.Z. provided the methodology; J.S. I.A.M.B. M.M. F.A. L.S. M.H. T.E. T.N. J.J. M.F. A.E. M.S. R.D. F.G. and J.Z. performed the investigations; and J.S. and J.Z. wrote the manuscript with input from all coauthors.
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:
© 2023 The American Society of Hematology