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.
All supplemental data are available openly via Zenodo (https://doi.org/10.5281/zenodo. 4321824). Mass spectrometry proteomics data are available via PRIDE (PXD019708). Gene expression and chromatin dynamics data are available via Gene Expression Omnibus (GSE163470).
Supplementary Data forZenodo, 4321824.
Definition of aberrant MYB CBP/P300 complex in AMLPRIDE, PXD019708.
Convergent organization of aberrant MYB complexes controls oncogenic gene expression in acute myeloid leukemiaNCBI Gene Expression Omnibus, GSE163470.
- Alex Kentsis
- Alex Kentsis
- Lauren Forbes
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France
© 2021, Takao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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