title: Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia.
abstract: Identification of the targets of mixed lineage leukemia (MLL) fusion genes will assist in understanding the biology of MLL fusion gene leukemias and in development of better therapies. Numerous studies have implicated HOXA9 as one of the possible targets of MLL fusion proteins. To determine if HOXA9 was required for leukemia development by MLL fusion genes, we compared the effects of the Mll-AF9 knock-in mutation in mice in the presence or absence of Hoxa9. Both groups of mice showed myeloid expansion at 8 weeks and then developed myeloid leukemia with a similar incidence and time course. The leukemia in the mice lacking Hoxa9 generally displayed a more immature myeloid phenotype than that in the mice that were wild-type for Hoxa9. Gene expression profiling revealed that expression of Mll-AF9 led to overexpression of Hoxa5, Hoxa6, Hoxa7, Hoxa9, and Hoxa10. Thus, genes of the Hox-a cluster are important in defining the phenotype but not the incidence of Mll-AF9 leukemia. These results demonstrate that the Mll-AF9 fusion gene disrupts the expression of several Hox genes, none of which as a single gene is likely to be necessary for development of leukemia. Instead, we propose that the "Hox code" minimally defined by the Hoxa5-a9 cluster is central to MLL leukemogenesis.
authors: Department of Pediatrics, University of Minnesota, Minneapolis, USA.
authors: Ashish R
authors: AR
authors: Kumar
authors: Wendy A
authors: WA
authors: Hudson
authors: Weili
authors: W
authors: Chen
authors: Ritsuo
authors: R
authors: Nishiuchi
authors: Qing
authors: Q
authors: Yao
authors: John H
authors: JH
authors: Kersey
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002469:Cell Separation; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D007938:Leukemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D012313:RNA / Q000378:metabolism; D013997:Time Factors
chemical_list: D018398:Homeodomain Proteins; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D012313:RNA