An essential role for MYB in driving oncogenic EVI1 expression in enhancer-rearranged leukemias

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 pinpoint a single regulatory element in the translocated GATA2 enhancer that is critically required for aberrant EVI1 expression while being dispensable for GATA2 expression from its endogenous locus. This element contains a DNA binding motif for the transcription factor MYB that heavily occupies this site specifically at the translocated allele. MYB knockout as well as peptidomimetic blockade of p300-dependent MYB function 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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001006821	ChIP-seq was conducted in blasts from patients with t(3;3) AML to assess differences of the GATA2 super-enhancer between the translocated allele and the non-translocated allele. The dataset includes 2x H3K27ac ChIP-seq and 1x MYB ChIP-seq. ChIP samples were processed according to the Illumina TruSeq ChIP Sample Preparation Protocol (Illumina) or Diagenode Library V3 preparation protocol (Diagenode) and either sequenced single-end (1x 50 bp) on the HiSeq 2500 platform (Illumina) or paired-end (2x100 bp) on the Novaseq 6000 platform (Illumina). Briefly, reads were aligned to the human reference genome build hg19 with bowtie for single-end runs and bowtie2 for paired-end runs.	Illumina HiSeq 2500 Illumina NovaSeq 6000	2

Publications	Citations
Selective Requirement of MYB for Oncogenic Hyperactivation of a Translocated Enhancer in Leukemia. Smeenk L, Ottema S, Mulet-Lazaro R, Ebert A, Havermans M, Varea AA, Fellner M, Pastoors D, van Herk S, Erpelinck-Verschueren C, Grob T, Hoogenboezem RM, Kavelaars FG, Matson DR, Bresnick EH, Bindels EM, Kentsis A, Zuber J, Delwel R. Cancer Discov 11: 2021 2868-2883	17