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Partial TCRB Gene Rearrangement Leads to Expansion of Thymocytes with Differentiation of B and T Lymphocytes and Fusion Gene Impairs NUP 98-HOXD 13 A

Expression of a NUP98-HOXD13 (NHD13) fusion gene leads to myelodysplastic syndrome in mice. In addition to ineffective hemato-poiesis, 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. T he myelodysplastic syndromes (MDS) 6 represent a heterogeneous group of clonal disorders of hematopoiesis, characterized by peripheral blood (PB) cytopenias, hyper-cellular, dysplastic bone marrow (BM), and a predilection for transformation to acute myelogenous leukemia. The assertion that MDS is a clonal disease is supported by observations that demonstrate over 50% of patients with MDS have one or more clonal cytogenetic abnormalities (1), as well as studies demonstrating clonal X inactivation in informative female MDS patients (2). The involvement of the lymphoid compartment as a part of the MDS clone has been the topic of some debate. Patients with MDS often have a mild degree of lymphopenia, especially involving T lymphocytes (3). In addition, although rare, there are numerous case reports of acute lymphoblastic leukemia evolving from MDS (4), suggesting the potential for the MDS clone to produce lym-phoid cells. However, lymphocytes from patients with trisomy 8 or monosomy 7, two common cytogenetic abnormalities associated with MDS, typically do not contain the cytogenetic abnormality …