SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia

J. Bu, A. Chen, X. Yan, F. He, Y. Dong, Y. Zhou, J. He, D. Zhan, P. Lin, Y. Hayashi, Y. Sun, Y. Zhang, Z. Xiao, H. L. Grimes, Q. F. Wang, G. Huang

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.

Original languageEnglish (US)
Pages (from-to)890-899
Number of pages10
JournalLeukemia
Volume32
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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