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

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 inexplica...

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Autores principales: Richter, William F, Shah, Rohan N, Ruthenburg, Alexander J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315800/
https://www.ncbi.nlm.nih.gov/pubmed/34263728
http://dx.doi.org/10.7554/eLife.64960
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author Richter, William F
Shah, Rohan N
Ruthenburg, Alexander J
author_facet Richter, William F
Shah, Rohan N
Ruthenburg, Alexander J
author_sort Richter, William F
collection PubMed
description 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-signaling, 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.
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spelling pubmed-83158002021-07-28 Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia Richter, William F Shah, Rohan N Ruthenburg, Alexander J eLife Cancer Biology 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-signaling, 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. eLife Sciences Publications, Ltd 2021-07-15 /pmc/articles/PMC8315800/ /pubmed/34263728 http://dx.doi.org/10.7554/eLife.64960 Text en © 2021, Richter et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Richter, William F
Shah, Rohan N
Ruthenburg, Alexander J
Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
title Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
title_full Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
title_fullStr Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
title_full_unstemmed Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
title_short Non-canonical H3K79me2-dependent pathways promote the survival of MLL-rearranged leukemia
title_sort non-canonical h3k79me2-dependent pathways promote the survival of mll-rearranged leukemia
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315800/
https://www.ncbi.nlm.nih.gov/pubmed/34263728
http://dx.doi.org/10.7554/eLife.64960
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