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A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement.

ABSTRACT: Expression of a NUP98-HOXD13 (NHD13) fusion gene leads to myelodysplastic syndrome in mice. In addition to ineffective hematopoiesis, we observed that NHD13 mice were lymphopenic; the lymphopenia was due to a decrease in both T and B lymphocytes. Although the pro-B cell (B220(+)/CD43(+)) populations from the NHD13 and wild-type mice were similar, the NHD13 mice showed decreased pre-B cells (B220(+)/CD43(-)), indicating impaired differentiation at the pro-B to pre-B stage. Thymi from NHD13 mice were smaller and overexpressed Hoxa cluster genes, including Hoxa7, Hoxa9, and Hoxa10. In addition, the NHD13 thymi contained fewer thymocytes, with an increased percentage of CD4(-)/CD8(-) (double-negative (DN)) cells and a decreased percentage of CD4(+)/CD8(+) (double-positive) cells; the DN1/DN2 population was increased and the DN3/DN4 population was decreased, suggesting a partial block at the DN2 to DN3 transition. To determine clonality of the thymocytes, we used degenerate RT-PCR to identify clonal Tcrb gene rearrangements. Five of six NHD13 thymi showed an unusual Tcrb gene rearrangement pattern with common, clonal DJ rearrangements, but distinct V-D junctions, suggesting a marked clonal expansion of thymocytes that had undergone a DJ rearrangement, but not completed a VDJ rearrangement. Taken together, these findings demonstrate that expression of the NHD13 transgene inhibits lymphoid as well as myeloid and erythroid differentiation, results in overexpression of Hoxa cluster genes, and leads to a precursor T cell lymphoblastic leukemia/lymphoma.

SUBMITTER: Choi CW

PROVIDER: S-EPMC3422874 | biostudies-other | 2009 Nov

REPOSITORIES: biostudies-other

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A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement.

Choi Chul Won CW Chung Yang Jo YJ Slape Christopher C Aplan Peter D PD

Journal of immunology (Baltimore, Md. : 1950) 20091019 10

Expression of a NUP98-HOXD13 (NHD13) fusion gene leads to myelodysplastic syndrome in mice. In addition to ineffective hematopoiesis, we observed that NHD13 mice were lymphopenic; the lymphopenia was due to a decrease in both T and B lymphocytes. Although the pro-B cell (B220(+)/CD43(+)) populations from the NHD13 and wild-type mice were similar, the NHD13 mice showed decreased pre-B cells (B220(+)/CD43(-)), indicating impaired differentiation at the pro-B to pre-B stage. Thymi from NHD13 mice w ...[more]

PMID: 19841179

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Project description:BACKGROUND: The nucleoporin gene NUP98 is rearranged in more than 27 chromosomal abnormalities observed in childhood and adult, de novo and therapy-related acute leukemias of myeloid and T-lymphoid origins, resulting in the creation of fusion genes and the expression of chimeric proteins. We report here the functional analysis of the NUP98-coiled-coil domain-containing protein 28A (NUP98-CCDC28A) fusion protein, expressed as the consequence of a recurrent t(6;11)(q24.1;p15.5) translocation. DESIGN AND METHODS: To gain insight into the function of the native CCDC28A gene, we collected information on any differential expression of CCDC28A among normal hematologic cell types and within subgroups of acute leukemia. To assess the in vivo effects of the NUP98-CCDC28A fusion, NUP98-CCDC28A or full length CCDC28A were retrovirally transduced into primary murine bone marrow cells and transduced cells were next transplanted into sub-lethally irradiated recipient mice. RESULTS: Our in silico analyses supported a contribution of CCDC28A to discrete stages of murine hematopoietic development. They also suggested selective enrichment of CCDC28A in the French-American-British M6 class of human acute leukemia. Primary murine hematopoietic progenitor cells transduced with NUP98-CCDC28A generated a fully penetrant and transplantable myeloproliferative neoplasm-like myeloid leukemia and induced selective expansion of granulocyte/macrophage progenitors in the bone marrow of transplanted recipients, showing that NUP98-CCDC28A promotes the proliferative capacity and self-renewal potential of myeloid progenitors. In addition, the transformation mediated by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, a feature shared by a diverse set of NUP98 fusions. CONCLUSIONS: Our results demonstrate that the recurrent NUP98-CCDC28A is an oncogene that induces a rapid and transplantable myeloid neoplasm in recipient mice. They also provide additional evidence for an alternative leukemogenic mechanism for NUP98 oncogenes.

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A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement.

Publications

A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement.

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