Mechanisms of transcriptional regulation by MLL and its disruption in acute leukemia.
Fusion of the mixed lineage leukemia protein (MLL) to one of over 50 different translocation partners converts it into a potent leukemogenic oncoprotein. The resulting fusion proteins transform primarily through upregulation of A-cluster Hox genes, including Hoxa9 and the Hox cofactor Meis1. Considerable progress has been made in delineating the differences between normal Hox gene regulation by MLL and deregulated transcription in MLL-induced leukemias. Some MLL translocation partners dimerize the truncated MLL molecule. Other translocation partners appear to recruit nuclear coactivator complexes that have diverse enzymatic activities that impinge on transcriptional elongation pathways. These enzymatic activities, including RNA polymerase II phosphorylation as well as histone H3 lysine 79 methylation present attractive targets for the development of future MLL-directed therapy.
Dou
Yali
Y
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-5602, USA.
Hess
Jay L
JL
D000818:Animals; D019175:DNA Methylation; D004195:Disease Models, Animal; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D019891:Leukopoiesis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics*
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; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase