TY - JOUR
T1 - SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia
AU - Bu, J.
AU - Chen, A.
AU - Yan, X.
AU - He, F.
AU - Dong, Y.
AU - Zhou, Y.
AU - He, J.
AU - Zhan, D.
AU - Lin, P.
AU - Hayashi, Y.
AU - Sun, Y.
AU - Zhang, Y.
AU - Xiao, Z.
AU - Grimes, H. L.
AU - Wang, Q. F.
AU - Huang, G.
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85044673897&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044673897&partnerID=8YFLogxK
U2 - 10.1038/leu.2017.339
DO - 10.1038/leu.2017.339
M3 - Article
C2 - 29249820
AN - SCOPUS:85044673897
SN - 0887-6924
VL - 32
SP - 890
EP - 899
JO - Leukemia
JF - Leukemia
IS - 4
ER -