Peptidomimetic blockade of MYB in acute myeloid leukemia

Nature Communications
Kavitha RamaswamyAlex Kentsis

Abstract

Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYB:CBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYB:CBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.

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May 30, 2019·Leukemia·Elena Armenteros-MonterrosoOwen Williams
Nov 8, 2019·Blood·Katie A FennellMark A Dawson
Oct 9, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Wenxing GuZhiyuan Zhong
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Oct 14, 2019·Oral Oncology·Yue JiangFrederic J Kaye
Apr 25, 2018·Oncology Research·Xiyan SunErbiao Liu

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Datasets Mentioned

BETA
GSE94242
GSE107078

Methods Mentioned

BETA
fluorescence microscopy
microscale thermophoresis
immunoprecipitation
RNA-seq
ChIP-seq
ChIP-PCR
acetylation
PCR
flow cytometry
xenograft

Software Mentioned

STAR
DESeq2
ViiA
Simulaid
MACS
RESPA
BEDTools
Maestro

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