dissection of the transformation of primary human hematopoietic cells by the oncogene nup98-hoxa9解剖的变换主要人类造血细胞的癌基因nup98-hoxa9.pdfVIP

Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9 1,2 1 1,2 2 2 Enas R. Yassin , Nayan J. Sarma , Anmaar M. Abdul-Nabi , James Dombrowski , Ye Han , Akiko Takeda1,2, Nabeel R. Yaseen1,2* 1 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America 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 (C