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

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