ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia.

Journal Article

Unlabelled

Numerous studies in multiple systems support that histone H3 lysine 36 dimethylation (H3K36me2) is associated with transcriptional activation; however, the underlying mechanisms are not well defined. Here, we show that the H3K36me2 chromatin mark written by the ASH1L histone methyltransferase is preferentially bound in vivo by LEDGF, a mixed-lineage leukemia (MLL)-associated protein that colocalizes with MLL, ASH1L, and H3K36me2 on chromatin genome wide. Furthermore, ASH1L facilitates recruitment of LEDGF and wild-type MLL proteins to chromatin at key leukemia target genes and is a crucial regulator of MLL-dependent transcription and leukemic transformation. Conversely, KDM2A, an H3K36me2 demethylase and Polycomb group silencing protein, antagonizes MLL-associated leukemogenesis. Our studies are the first to provide a basic mechanistic insight into epigenetic interactions wherein placement, interpretation, and removal of H3K36me2 contribute to the regulation of gene expression and MLL leukemia, and suggest ASH1L as a novel target for therapeutic intervention.

Significance

Epigenetic regulators play vital roles in cancer pathogenesis and represent a new frontier in therapeutic targeting. Our studies provide basic mechanistic insight into the role of H3K36me2 in transcription activation and MLL leukemia pathogenesis and implicate ASH1L histone methyltransferase as a promising target for novel molecular therapy. Cancer Discov; 6(7); 770-83. ©2016 AACR.See related commentary by Balbach and Orkin, p. 700This article is highlighted in the In This Issue feature, p. 681.

Full Text

Duke Authors

Cited Authors

  • Zhu, L; Li, Q; Wong, SHK; Huang, M; Klein, BJ; Shen, J; Ikenouye, L; Onishi, M; Schneidawind, D; Buechele, C; Hansen, L; Duque-Afonso, J; Zhu, F; Martin, GM; Gozani, O; Majeti, R; Kutateladze, TG; Cleary, ML

Published Date

  • July 2016

Published In

Volume / Issue

  • 6 / 7

Start / End Page

  • 770 - 783

PubMed ID

  • 27154821

Pubmed Central ID

  • 27154821

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

International Standard Serial Number (ISSN)

  • 2159-8274

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.cd-16-0058

Language

  • eng