title: MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome.
abstract: MLL encodes a histone methyltransferase that is critical in maintaining gene expression during embryonic development and hematopoiesis. 11q23 translocations result in the formation of chimeric MLL fusion proteins that act as potent drivers of acute leukemia. However, it remains unclear what portion of the leukemic genome is under the direct control of MLL fusions. By comparing patient-derived leukemic cell lines, we find that MLL fusion-bound genes are a small subset of that recognized by wild-type MLL. In an inducible MLL-ENL model, MLL fusion protein binding and changes in H3K79 methylation are limited to a specific portion of the genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among 223 MLL-ENL-bound genes, only 12 demonstrate a significant increase in mRNA expression on induction of the fusion protein. In addition to Hoxa9 and Meis1, this includes Eya1 and Six1, which comprise a heterodimeric transcription factor important in several developmental pathways. We show that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro and collaborates with Six1 in hematopoietic transformation assays. Altogether, our data suggest that MLL fusions contribute to the development of acute leukemia through direct activation of a small set of target genes.
authors.affiliation: Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Qian-Fei
authors.initials: QF
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Wu
authors.forename: Shuangli
authors.initials: S
authors.lastname: Mi
authors.forename: Fuhong
authors.initials: F
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.forename: Jingfang
authors.initials: J
authors.lastname: Dong
authors.forename: Roger T
authors.initials: RT
authors.lastname: Luo
authors.forename: Ryan
authors.initials: R
authors.lastname: Mattison
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Kaberlein
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Hongkai
authors.initials: H
authors.lastname: Ji
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thirman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C099236:SIX1 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases