Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia.

Masahiro Uni,Michael G Kharas,Christopher R Vakoc,Gerard Minuesa,Richard P Koche,Robert K Bradley,Celine Chen,Alex Kentsis,Yusuke Tarumoto,Lauren Forbes,Jose Mario Bello Pineda,Sumiko Takao,Shuyuan Cheng,Paolo Cifani

doi:10.7554/elife.65905

Abstract

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

Highlights

Gene dysregulation is one of the most prevalent features in human cancers (Bradner et al, 2017)
By rapid and selective peptidomimetic interference with the binding of CREB-binding protein (CBP)/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in acute myeloid leukemias (AML) cells, which is associated at least in part with their inappropriate expression
Dysregulated gene expression is a near universal feature of all human cancers. This is relevant for leukemias which are frequently caused by mutations of genes encoding transcription and chromatin remodeling factors

Summary

Introduction

Gene dysregulation is one of the most prevalent features in human cancers (Bradner et al, 2017) In many tumors, this is due to the pathogenic mutations of promoters, enhancers, and genes encoding either transcription factors or factors that regulate chromatin and gene expression. Approximately 25% of adult and childhood AMLs, including both MLLrearranged and non-rearranged cases, require aberrant activation of the transcription factor MEF2C, conferring susceptibility to MARK and SIK inhibitors, which are currently being explored for clinical trials for patients (Brown et al, 2018; Tarumoto et al, 2018; Vakoc & Kentsis, 2018). Nearly 50% of examined AML specimens exhibit aberrant activation of HGF/MET/FGFR signaling (Kentsis et al, 2012), and are being currently targeted therapeutically in the ongoing clinical trial of combined MET and FGFR inhibitors in patients with relapsed or refractory AML (ClinicalTrials.gov Identifier NCT03125239). There is intense interest in defining shared molecular dependencies controlling leukemogenic gene expression in AML that can provide effective therapeutic options for patients

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