ASH1L Links Histone H3 Lysine 36 Dimethylation to MLL Leukemia.

Published

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