Role of a Conserved Helicase Motif in the Transformation of Primary Human CD34+ Cells by the NUP98-DDX10 Oncogene.

Abstract 2966

Poster Board II-942

NUP98 gene rearrangements occur in acute myeloid leukemia and other hematopoietic malignancies, and result in the expression of fusion proteins. One of the most frequent NUP98 fusions is NUP98-DDX10 that consists of an N-terminal portion of NUP98 and a C-terminal segment of DDX10, a putative DEAD-box RNA helicase. Here we express NUP98-DDX10 in primary human CD34+ hematopoietic cells and show that it localizes within the nucleus in a punctate distribution. It dramatically increases the proliferation and self-renewal of primary human CD34+ cells and disrupts their erythroid and myeloid differentiation. Expression gene profiling shows dysregulation of many genes by NUP98-DDX10 in primary human CD34+ cells starting within 6 h. Comparison of the dysregulome of NUP98-DDX10 to that of another leukemogenic NUP98 fusion, NUP98-HOXA9, reveals a number of genes dysregulated by both oncoproteins, including HOX genes, COX-2, MYCN, angiopoietin-1, renin, HEY1, SOX4, and others, that may account for the induction of AML by these and other NUP98 fusion oncogenes. The HRAGRTAR sequence in the DDX10 portion of NUP98-DDX10 corresponds to a major motif shared by DEAD-box RNA helicases that is required for their ATP binding/hydrolysis, RNA-binding, and helicase functions. Mutating this motif diminished the transforming ability of NUP98-DDX10, indicating that it plays a role in leukemogenesis. These data demonstrate for the first time the transforming ability of NUP98-DDX10 and show that it is partially dependent on one of the consensus helicase motifs of DDX10. They also point to common pathways that may underlie leukemogenesis by different NUP98 fusions.