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

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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

1. Richter WF
(2020) RNA-seq analysis of 10 nM pinometostat vs. DMSO-treated MV4;11 cells
NCBI Gene Expression Omnibus GSE162441.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162441
1. Richter WF
2. Shah RN
(2020) ICeChIP-seq of H3K79me2, H3K4me3, H3K27me3, H3K36me3 from MV4;11 cells treated with 10 nM pinometostat or DMSO
NCBI Gene Expression Omnibus GSE162441.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162441

Article and author information

Author details

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.
Rohan N Shah

Pritzker School of Medicine, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.