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 R Vakoc
  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 R Vakoc

    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.

Metrics

  • 5,144
    Page views
  • 588
    Downloads
  • 27
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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 R Vakoc
  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

Share this article

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

Further reading

    1. Cancer Biology
    Sen Qin, Yawei Xu ... Zheng Zhang
    Research Article

    Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.

    1. Cancer Biology
    Qiaomu Tian, Peng Zhang ... Anita S Chong
    Research Article Updated

    Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, (E)–19-[(1’-benzoyloxy-1’-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and used human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 hr and ~8,000 DEGs at 12 hr. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. Thus, CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.