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

Takao, Sumiko, Forbes, Lauren, Uni, Masahiro, Cheng, Shuyuan, Pineda, Jose Mario Bello, Tarumoto, Yusuke, Cifani, Paolo, Minuesa, Gerard, Chen, Celine, Kharas, Michael G, Bradley, Robert K, Vakoc, Christopher R, Koche, Richard P, Kentsis, Alex (February 2021) Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia. eLife, 10. pp. 1-46. ISSN 2050-084X

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URL: https://www.ncbi.nlm.nih.gov/pubmed/33527899
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.

Item Type: Paper
Subjects: diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
diseases & disorders > cancer > cancer types > leukemia
CSHL Authors:
Communities: CSHL labs > Vakoc lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 2 February 2021
Date Deposited: 05 May 2021 13:44
Last Modified: 05 May 2021 13:44
PMCID: PMC7886351
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39987

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