title: Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia.
abstract: The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4-ENL-P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia. However, the functional interrelationship among those 3 complexes in leukemic transformation remains largely elusive. Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberrantly inducing both AEP-dependent transcriptional activation and DOT1L-dependent transcriptional maintenance, mostly in the absence of PRC1, to fully transform hematopoietic progenitors. These results reveal a cooperative transcriptional activation mechanism of AEP and DOT1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion-AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okuda
authors.forename: Boban
authors.initials: B
authors.lastname: Stanojevic
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsui
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015321:Gene Rearrangement; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C489900:Aff1 protein, mouse; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; C473477:DOT1L protein, human; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse