Molecular interactions of the oncogene NUP98-HOXA9 (153.31)

Abstract

Abstract NUP98-HOXA9 is the prototype of the fusion oncoproteins that result from NUP98 gene rearrangements and are associated with acute myeloid leukemia. It consists of an N-terminal FG-rich portion of the nucleoporin NUP98 fused to a C-terminal portion of the homeobox protein HOXA9, and acts as an aberrant transcription factor. Using a yeast two-hybrid assay we have identified several interacting partners of NUP98-HOXA9 including Dynein Light Chain 1 (DYNLT1) and Amino-terminal Enhancer of Split (AES). We showed that the FG repeat region of NUP98 is critical for these interactions. In addition, we found that DYNLT1 localizes to the nuclear periphery, interacts with other nucleoporins and these interactions are dependent on the C-terminal of DYNLT1. Knockdown of DYNLT1 resulted in reduction of the ability of NUP98-HOXA9 to activate its target promoters. AES localizes primarily to the interior of the nucleus and showed a strong interaction with NUP98 but not with other FG repeat nucleoporins. AES augmented the transcriptional activity of NUP98-HOXA9. In the presence of NUP98-HOXA9, AES caused an increase in long-term proliferation of primary human CD34+ cells with an increase in the numbers of primitive cells. AES caused a shift away from the erythroid lineage in primary CD34+ cells, thus counteracting the effects of NUP98-HOXA9 on differentiation. These data establish that DYNLT1 and AES interact and cooperate with NUP98-HOXA9 in transcriptional regulation and cell transformation.