title: NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights.
abstract: Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodomain proteins, and at least 5 NUP98 fusions involve known histone-modifying genes. Several of the NUP98 fusions, including NUP98-homeobox (HOX)A9, NUP98-HOXD13, and NUP98-JARID1A, have been used to generate animal models of both lymphoid and myeloid malignancy; these models typically up-regulate HOXA cluster genes, including HOXA5, HOXA7, HOXA9, and HOXA10. In addition, several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of hematopoietic stem or progenitor cells, providing a potential mechanism for malignant transformation.
authors.affiliation: Leukemia Biology Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Sheryl M
authors.initials: SM
authors.lastname: Gough
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Slape
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D022022:Nuclear Pore / Q000502:physiology; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D057345:Sequence Inversion; D014158:Transcription, Genetic; D014178:Translocation, Genetic
chemical_list: D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D015514:Oncogene Proteins, Fusion