Dimerization of MLL fusion proteins immortalizes hematopoietic cells.
MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.
Martin
Mary Ellen
ME
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Milne
Thomas A
TA
Bloyer
Sebastien
S
Galoian
Karine
K
Shen
Weiping
W
Gibbs
Denise
D
Brock
Hugh W
HW
Slany
Robert
R
Hess
Jay L
JL
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D015973:Gene Expression Regulation, Leukemic; D006413:Hematopoietic System / Q000378:metabolism / Q000473:pathology*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D012190:Retroviridae; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; C492047:Hoxa7 protein, mouse; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse