Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia

  1. William F Richter
  2. Rohan N Shah
  3. Alexander J Ruthenburg  Is a corresponding author
  1. University of Chicago, United States

Abstract

MLL-rearranged leukemia depends on H3K79 methylation. Depletion of this transcriptionally-activating mark by DOT1L deletion or high concentrations of the inhibitor pinometostat downregulates HOXA9 and MEIS1, and consequently reduces leukemia survival. Yet some MLL-rearranged leukemias are inexplicably susceptible to low-dose pinometostat, far below concentrations that downregulate this canonical proliferation pathway. In this context, we define alternative proliferation pathways that more directly derive from H3K79me2 loss. By ICeChIP-seq, H3K79me2 is markedly depleted at pinometostat-downregulated and MLL-fusion targets, with paradoxical increases of H3K4me3 and loss of H3K27me3. Although downregulation of polycomb components accounts for some of the proliferation defect, transcriptional downregulation of FLT3 is the major pathway. Loss-of-FLT3-function recapitulates the cytotoxicity and gene expression consequences of low-dose pinometostat, whereas overexpression of constitutively active STAT5A, a target of FLT3-ITD-signalling, largely rescues these defects. This pathway also depends on MLL1, indicating combinations of DOT1L, MLL1 and FLT3 inhibitors should be explored for treating FLT3-mutant leukemia.

Data availability

ICeChIP-seq and RNA-seq data have been deposited in GEO under the accession code GSE162441.

The following data sets were generated

Article and author information

Author details

  1. William F Richter

    Molecular Genetics and Cell Biology/ Biochemistry and Molecular Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rohan N Shah

    Pritzker School of Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexander J Ruthenburg

    Molecular Genetics and Cell Biology/ Biochemistry and Molecular Biology, University of Chicago, Chicago, United States
    For correspondence
    aruthenburg@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2709-4564

Funding

American Cancer Society (130230-RSG-16-248-01-DMC)

  • Alexander J Ruthenburg

National Institutes of Health (R01-GM115945)

  • Alexander J Ruthenburg

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

Reviewing Editor

  1. Xiaobing Shi, Van Andel Institute, United States

Version history

  1. Received: November 17, 2020
  2. Preprint posted: December 4, 2020 (view preprint)
  3. Accepted: July 5, 2021
  4. Accepted Manuscript published: July 15, 2021 (version 1)
  5. Version of Record published: July 27, 2021 (version 2)

Copyright

© 2021, Richter 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. William F Richter
  2. Rohan N Shah
  3. Alexander J Ruthenburg
(2021)
Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
eLife 10:e64960.
https://doi.org/10.7554/eLife.64960

Share this article

https://doi.org/10.7554/eLife.64960

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