Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9.

Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9.

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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 Inlet Hose 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 GF BROWN RICE LOAF 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.