Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential

Aravinda Kuntimaddi, Nicholas J. Achille, Jeremy Thorpe, Alyson A. Lokken, Ritambhara Singh, Charles S. Hemenway, Mazhar Adli, Nancy J. Zeleznik-Le*, John H. Bushweller

*Corresponding author for this work

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The MLL gene is a common target of chromosomal translocations found in human leukemia. MLL-fusion leukemia has a consistently poor outcome. One of the most common translocation partners is AF9 (MLLT3). MLL-AF9 recruits DOT1L, a histone 3 lysine 79 methyltransferase (H3K79me1/me2/me3), leading to aberrant gene transcription. We show that DOT1L has three AF9 binding sites and present the nuclear magnetic resonance (NMR) solution structure of a DOT1L-AF9 complex. We generate structure-guided point mutations and find that they have graded effects on recruitment of DOT1L to MLL-AF9. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses of H3K79me2 and H3K79me3 show that graded reduction of the DOT1L interaction with MLL-AF9 results in differential loss of H3K79me2 and me3 at MLL-AF9 target genes. Furthermore, the degree of DOT1L recruitment is linked to the level of MLL-AF9 hematopoietic transformation.

Original languageEnglish (US)
Pages (from-to)808-820
Number of pages13
JournalCell reports
Volume11
Issue number5
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kuntimaddi, A., Achille, N. J., Thorpe, J., Lokken, A. A., Singh, R., Hemenway, C. S., Adli, M., Zeleznik-Le, N. J., & Bushweller, J. H. (2015). Degree of Recruitment of DOT1L to MLL-AF9 Defines Level of H3K79 Di- and Tri-methylation on Target Genes and Transformation Potential. Cell reports, 11(5), 808-820. https://doi.org/10.1016/j.celrep.2015.04.004