title: Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1.
abstract: The association between acute myeloid leukaemia (AML) and the aberrant expression of Hoxa9 is evidenced by (1) proviral activation of Hoxa9 and Meis1 in BXH-2 murine AML, (2) formation of the chimeric Nup98-HoxA9 transactivator protein as a consequence of the t(7;11) translocation in human AML, and (3) the strong expression of HoxA9 and Meis1 in human AML. In mouse models, enforced retroviral expression of Hoxa9 alone in marrow is not sufficient to cause rapid AML, while co-expression of Meis1 and Hoxa9 induces rapid AML. In contrast, retroviral expression of Nup98-HoxA9 is sufficient to cause rapid AML in the absence of enforced Meis1 expression. Previously, we demonstrated that Hoxa9 could block the differentiation of murine marrow progenitors cultured in granulocyte-macrophage colony-simulating factor (GM-CSF). These progenitors lacked Meis1 expression, could not proliferate in stem cell factor (SCF), but could differentiate into neutrophils when switched into granulocyte colony-simulating factor (G-CSF). Ectopic expression of Meis1 in these Hoxa9 cells suppressed their G-CSF-induced differentiation, permitted proliferation in SCF, and therein offered a potential explanation of cooperative function. Because Meis1 binds N-terminal Hoxa9 sequences that are replaced by Nup98, we hypothesized that Nup98-HoxA9 might consolidate the biochemical functions of both Hoxa9 and Meis1 on target gene promoters and might evoke their same lymphokine-responsive profile in immortalized progenitors. Here we report that Nup98-HoxA9, indeed mimicks Hoxa9 plus Meis1 coexpression - it immortalizes myeloid progenitors, prevents differentiation in response to GM-CSF, IL-3, G-CSF, and permits proliferation in SCF. Unexpectedly, however, Nup98-Hoxa9 also enforced strong transcription of the cellular Hoxa9, Hoxa7 and Meis1 genes at levels similar to those found in mouse AML's generated by proviral activation of Hoxa9 and Meis1. Using Hoxa9(-/-) marrow, we demonstrate that expression of Hoxa9 is not required for myeloid immortalization by Nup98-HoxA9. Rapid leukaemogenesis by Nup98-HoxA9 may therefore result from both the intrinsic functions of Nup98-HoxA9, as well as of those of coexpressed HOX and MEIS1 genes.
authors.affiliation: University of California School of Medicine, Department of Pathology 9500 Gilman Drive, La Jolla, California, CA 92093-0612, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Calvo
authors.forename: David B
authors.initials: DB
authors.lastname: Sykes
authors.forename: Martina P
authors.initials: MP
authors.lastname: Pasillas
authors.forename: Mark P
authors.initials: MP
authors.lastname: Kamps
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000209:etiology; D051379:Mice; D008807:Mice, Inbred BALB C; D005810:Multigene Family; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D019089:Stem Cell Factor / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology; D014178:Translocation, Genetic
chemical_list: D016207:Cytokines; D018398:Homeodomain Proteins; D007377:Interleukin-3; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C400441:NUP98-HOXA9 fusion protein, human; D009363:Neoplasm Proteins; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; C097899:homeobox protein HOXA9; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor