Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia

Leonie Smeenk, Sophie Ottema, Roger Mulet-Lazaro, Anja Ebert, Marije Havermans, Andrea Arricibita Varea, Michaela Fellner, Dorien Pastoors, Stanley van Herk, Claudia Erpelinck-Verschueren, Tim Grob, Remco M. Hoogenboezem, Francois G. Kavelaars, Daniel R. Matson, Emery H. Bresnick, Eric M. Bindels, Alex Kentsis, Johannes Zuber, Ruud Delwel

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated GATA2 enhancer drives oncogenic expression of EVI1. We generated an
EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence
motifs essential for EVI1 transcription. Using this approach, we pinpointed a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression. This
element contained a DNA-binding motif for the transcription factor MYB, which specifically occupied
this site at the translocated allele and was dispensable for GATA2 expression. MYB knockout as well
as peptidomimetic blockade of CBP/p300-dependent MYB functions resulted in downregulation of
EVI1 but not of GATA2. Targeting MYB or mutating its DNA-binding motif within the GATA2 enhancer
resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven EVI1
transcription provides a potential entry point for therapy of inv(3)/t(3;3) AMLs.
Significance: We show a novel paradigm in which chromosomal aberrations reveal critical regulatory
elements that are nonfunctional at their endogenous locus. This knowledge provides a rationale to
develop new compounds to selectively interfere with oncogenic enhancer activity.
Original languageEnglish
Pages (from-to)2868-2883
JournalCancer Discovery
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2021

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