title: Insulin-like growth factor 1 is a direct HOXA9 target important for hematopoietic transformation.
abstract: HOX homeobox proteins are key oncogenic drivers in hematopoietic malignancies. Here we demonstrate that HOXA1, HOXA6 and predominantly HOXA9 are able to induce the production of insulin-like growth factor 1 (Igf1). In chromatin immunoprecipitations, HOXA9 bound directly to the putative promoter and a DNase-hypersensitive region in the first intron of the Igf1 gene. Transcription rates of the Igf1 gene paralleled HOXA9 activity. Primary cells transformed by HOXA9 expressed functional Igf1 receptors and activated the protein kinase Akt in response to Igf1 stimulation, suggesting the existence of an autocrine signaling loop. Genomic deletion of the Igf1 gene by Cre-mediated recombination increased sensitivity toward apoptosis after serum starvation. In addition, the leukemogenic potential of Igf1-negative, HOXA9-transformed cells was impaired, leading to a significant delay in disease development on transplantation into recipient animals.
authors.affiliation: Department of Genetics, University of Erlangen, Erlangen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Steger
authors.affiliation: Department of Genetics, University of Erlangen, Erlangen, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Füller
authors.affiliation: Department of Genetics, University of Erlangen, Erlangen, Germany.
authors.forename: M-P
authors.initials: MP
authors.lastname: Garcia-Cuellar
authors.affiliation: Department of Genetics, University of Erlangen, Erlangen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Hetzner
authors.affiliation: Department of Genetics, University of Erlangen, Erlangen, Germany.
authors.forename: R K
authors.identifier: 0000000220289759
authors.initials: RK
authors.lastname: Slany
mesh_terms: D000818:Animals; D017209:Apoptosis; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C498560:Hoxa6 protein, mouse; C097899:homeobox protein HOXA9