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

Abstract

In acute myeloid leukemia (AML) with inv(3)(q21;q26) or t(3;3)(q21;q26), a translocated <i>GATA2</i> enhancer drives oncogenic expression of <i>EVI1</i>. We generated an EVI1-GFP AML model and applied an unbiased CRISPR/Cas9 enhancer scan to uncover sequence motifs essential for <i>EVI1</i> transcription. Using this approach, we pinpointed a single regulatory element in the translocated <i>GATA2</i> enhancer that is critically required for aberrant <i>EVI1</i> 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 <i>GATA2</i> expression. <i>MYB</i> 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 <i>GATA2</i> enhancer resulted in myeloid differentiation and cell death, suggesting that interference with MYB-driven <i>EVI1</i> 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.<i>This article is highlighted in the In This Issue feature, p. 2659</i>.