title: A NUP98-HOXD13 leukemic fusion gene leads to impaired class switch recombination and antibody production.
abstract: Myelodysplastic syndrome is a clonal process characterized by ineffective hematopoiesis and progression to acute leukemia. Although many myelodysplastic syndrome and leukemic patients have compromised immunity, the role of underlying mutations in regulating immune function is poorly understood. Recent studies show that NUP98-HOXD13 (NHD13) fusion gene results in myelodysplastic syndrome and impairs lymphocyte differentiation in transgenic mice. In our studies, we sought to elucidate the mechanism by which NHD13 affects B-lymphocyte development and function. Based on our preliminary findings that transgenic mice had increased levels of IgM and reduced IgG1 and IgE, we hypothesized that the fusion gene might impair class switch recombination (CSR). Mice were immunologically challenged with dinitrophenol. NHD13 mice showed a marked reduction in B-lymphocyte differentiation in their bone marrow and spleen following dinitrophenol stimulation and had reduced production of dinitrophenol-specific antibodies. Spleen follicles from these mice were small and hypocellular, indicating failure of clonal expansion. When isolated NHD13 B lymphocytes were stimulated in vitro using Escherichia coli lipopolysaccharide or lipopolysaccharide + interleukin-4, they failed to undergo sufficient CSR and proliferation. Taken together, our findings show that expression of NUP98-HOXD13 impairs CSR and reduces the antibody-mediated immune response, in addition to its role in leukemia. Further delineation of the NUP98-HOXD13 transgene may reveal novel pathways involved in CSR.
authors.affiliation: Laboratory of Molecular Pathology, Virginia Tech, Blacksburg, VA 24061, USA.
authors.forename: Abdul Gafoor
authors.initials: AG
authors.lastname: Puthiyaveetil
authors.forename: Bettina
authors.initials: B
authors.lastname: Heid
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
authors.forename: Harm
authors.initials: H
authors.lastname: HogenEsch
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000502:physiology; D017578:Immunoglobulin Class Switching; D008231:Lymphopenia / Q000209:etiology; D038041:Lymphopoiesis; D051379:Mice; D008822:Mice, Transgenic; D028861:Nuclear Pore Complex Proteins / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology
chemical_list: C521093:NUP98-HOXD13 protein, human; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D015514:Oncogene Proteins, Fusion