title: HoxA9 regulated Bcl-2 expression mediates survival of myeloid progenitors and the severity of HoxA9-dependent leukemia.
abstract: Deregulated expression of Hox genes such as HoxA9 is associated with development of myeloproliferative disorders and leukemia and indicates a poor prognosis. To investigate the molecular mechanisms by which HoxA9 promotes immortalization of hematopoietic cells, we generated growth factor dependent myeloid cells in which HoxA9 expression is regulated by administration of 4-hydroxy-tamoxifen. Maintenance of HoxA9 overexpression is required for continued cell survival and proliferation, even in the presence of growth factors. We show for the first time that maintenance of Bcl-2 expression is critical for HoxA9-dependent immortalization and influences the latency of HoxA9-dependent leukemia. Hematopoietic cells lacking Bcl-2 were not immortalized by HoxA9 in vitro. Furthermore, deletion of Bcl-2 delayed the onset and reduced the severity of HoxA9/Meis1 and MLL-AF9 leukemias. This is the first description of a molecular link between HoxA9 and the regulation of Bcl-2 family members in acute myeloid leukemia.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Australia.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Brumatti
authors.forename: Marika
authors.initials: M
authors.lastname: Salmanidis
authors.forename: Chung H
authors.initials: CH
authors.lastname: Kok
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Bilardi
authors.forename: Jarrod J
authors.initials: JJ
authors.lastname: Sandow
authors.forename: Natasha
authors.initials: N
authors.lastname: Silke
authors.forename: Kylie
authors.initials: K
authors.lastname: Mason
authors.forename: Jolanda
authors.initials: J
authors.lastname: Visser
authors.forename: Anissa M
authors.initials: AM
authors.lastname: Jabbour
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic; D019254:Genes, bcl-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007377:Interleukin-3 / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018398:Homeodomain Proteins; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; C097899:homeobox protein HOXA9; D013629:Tamoxifen; C016601:afimoxifene; D016178:Granulocyte-Macrophage Colony-Stimulating Factor