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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 Rearrangement¹

Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20889

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

² C.W.C. and Y.J.C. contributed equally to this work.

³ Current address: Section of Oncology-Hematology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea.

⁴ Current address: Bone Marrow Research Laboratories, Royal Melbourne Hospital, Melbourne, Australia.

⁵ Address correspondence and reprint requests to Dr. Peter D. Aplan, Navy 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, MD 20889-5105. E-mail address: aplanp{at}mail.nih.gov

⁶ Abbreviations used in this paper: MDS, myelodysplastic syndrome; BM, bone marrow; DN, double negative; DP, double positive; PB, peripheral blood; PI, propidium iodide; pre-T LBL, precursor T cell lymphoblastic leukemia/lymphoma; RQ, real-time quantification; SP, single positive; WT, wild type.

⁷ The online version of this article contains supplemental material.