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.
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This work was supported by the National Natural Science Foundation of China (grant 81425003 and 91731302 to QFW, grant 81500142 to AC), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDA12010304 to QFW), the CFK (to GH), National Institutes of Health (NIH) (R21CA187276 to GH), the scholarship from China Scholarship Council (No. 201504910521 to JB), the Youth Innovation Promotion Association of Chinese Academy of Sciences (to FH), the Suzhou Key Laboratory for Pediatric Leukemia (SZS201615), Social Development Project of Jiangsu Province (CXTDA2017014 to SH), the Uehara Memorial Foundation for a Research Fellowship (to YH). We thank Dr Tao Cheng (Chinese Academy of Medical Sciences and Peking Union Medical College) for generously providing the Setd2 shRNAs.
QFW and GH designed the research; JB performed all the experiments and bioinformatics analysis; AC, XY, YD, Y-LZ, DZ, PL, YH, YZ, ZX helped with experiments; FH, JH and YS helped with bioinformatics analysis; JB, HLG, QFW and GH wrote the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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Bu, J., Chen, A., Yan, X. et al. SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia. Leukemia 32, 890–899 (2018). https://doi.org/10.1038/leu.2017.339
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