The PHD fingers of MLL block MLL fusion protein-mediated transformation.
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are associated with aggressive acute lymphoid and myeloid leukemias. These translocations are restricted to an 8.3-kb breakpoint region resulting in fusion of amino terminal MLL sequences in frame to 1 of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain (PHD) fingers and more carboxyl terminal MLL sequences. The function of the PHD fingers is obscure and their specific role in transformation has not been explored. Here we show that inclusion of the PHD fingers in the MLL fusion protein MLL-AF9 blocked immortalization of hematopoietic progenitors. Inclusion of 2 or more PHD fingers reduced association with the Hoxa9 locus and suppressed Hoxa9 up-regulation in hematopoietic progenitors. These data provide an explanation for why MLL translocation breakpoints exclude the PHD fingers and suggest a possible role for these domains in regulating the function of wild-type MLL.
Muntean
Andrew G
AG
Department ofPathology, University of Michigan Medical School, Ann Arbor, USA.
Giannola
Diane
D
Udager
Aaron M
AM
Hess
Jay L
JL
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D041722:Genes, Transgenic, Suicide / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D014161:Transduction, Genetic; D014410:Tumor Stem Cell Assay
D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
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