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

  1. Sumiko Takao
  2. Lauren Forbes
  3. Masahiro Uni
  4. Shuyuan Cheng
  5. Jose Mario Bello Pineda
  6. Yusuke Tarumoto
  7. Paolo Cifani
  8. Gerard Minuesa
  9. Celine Chen
  10. Michael G Kharas
  11. Robert K Bradley
  12. Christopher Vakoc, MD, PhD
  13. Richard P Koche
  14. Alex Kentsis  Is a corresponding author
  1. Memorial Sloan Kettering Cancer Center, United States
  2. Fred Hutchinson Cancer Research Center, United States
  3. Kyoto University, Japan
  4. Cold Spring Harbor Laboratory, United States

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.

Data availability

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).

The following data sets were generated

Article and author information

Author details

  1. Sumiko Takao

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  2. Lauren Forbes

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  3. Masahiro Uni

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  4. Shuyuan Cheng

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  5. Jose Mario Bello Pineda

    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1417-9200
  6. Yusuke Tarumoto

    Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6652-9618
  7. Paolo Cifani

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  8. Gerard Minuesa

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  9. Celine Chen

    SKI, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  10. Michael G Kharas

    Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
  11. Robert K Bradley

    Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8046-1063
  12. Christopher Vakoc, MD, PhD

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  13. Richard P Koche

    Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6820-5083
  14. Alex Kentsis

    Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    kentsisresearchgroup@gmail.com
    Competing interests
    Alex Kentsis, AK is a consultant for Novartis and Rgenta. A patent application related to this work has been submitted to the U.S. Patent and Trademark Office entitled 'Agents and methods for treating CREB binding protein-dependent cancers' (application PCT/US2017/059579)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8063-9191

Funding

National Institutes of Health (R01 CA204396)

  • Alex Kentsis

National Institutes of Health (P30 CA008748)

  • Alex Kentsis

National Institutes of Health (T32 GM073546)

  • Lauren Forbes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Irwin Davidson, Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Version history

  1. Received: December 18, 2020
  2. Accepted: February 1, 2021
  3. Accepted Manuscript published: February 2, 2021 (version 1)
  4. Accepted Manuscript updated: February 3, 2021 (version 2)
  5. Accepted Manuscript updated: February 4, 2021 (version 3)
  6. Version of Record published: February 16, 2021 (version 4)

Copyright

© 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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  1. Sumiko Takao
  2. Lauren Forbes
  3. Masahiro Uni
  4. Shuyuan Cheng
  5. Jose Mario Bello Pineda
  6. Yusuke Tarumoto
  7. Paolo Cifani
  8. Gerard Minuesa
  9. Celine Chen
  10. Michael G Kharas
  11. Robert K Bradley
  12. Christopher Vakoc, MD, PhD
  13. Richard P Koche
  14. Alex Kentsis
(2021)
Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia
eLife 10:e65905.
https://doi.org/10.7554/eLife.65905

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https://doi.org/10.7554/eLife.65905

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