title: Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9.
abstract: NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Enas R
authors.initials: ER
authors.lastname: Yassin
authors.forename: Nayan J
authors.initials: NJ
authors.lastname: Sarma
authors.forename: Anmaar M
authors.initials: AM
authors.lastname: Abdul-Nabi
authors.forename: James
authors.initials: J
authors.lastname: Dombrowski
authors.forename: Ye
authors.initials: Y
authors.lastname: Han
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeda
authors.forename: Nabeel R
authors.initials: NR
authors.lastname: Yaseen
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology*; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; C097899:homeobox protein HOXA9
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