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Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential.

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Kuntimaddi A,Achille NJ,Thorpe J,Lokken AA,Singh R,Hemenway CS,Adli M,Zeleznik-Le NJ,Bushweller JH

doi

10.1016/j.celrep.2015.04.004

subject

Has Abstract

pub_date

2015-05-05 00:00:00

pages

808-20

issue

5

issn

2211-1247

pii

S2211-1247(15)00379-4

journal_volume

11

pub_type

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