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Increased Expression of Germinal Center–Associated Nuclear Protein RNA-Primase Is Associated with Lymphomagenesis

Departments of ¹ Immunology, ² Cell Pathology, and ³ Diagnostic Radiology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan; ⁴ Department of Pathology, School of Medicine, Fukuoka University, Nanakuma, Jonan, Fukuoka, Japan; ⁵ Precursory Research for Embryonic Science and Technology and ⁶ Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

Requests for reprints: Nobuo Sakaguchi, Department of Immunology, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-8556, Japan. Phone: 81-96-373-5134; Fax: 81-96-373-5138; E-mail: nobusaka{at}kaiju.medic.kumamoto-u.ac.jp.

Lymphomas arise containing abnormalities of various differentiation stage-specific molecules. In the study reported here, we have shown abnormal up-regulation of germinal center B cell–associated GANP in various human lymphomas including mantle cell, diffuse large B cell, and Hodgkin lymphoma, by immunohistochemical analysis. To study the role of GANP in lymphomagenesis, we generated mutant mice (ganp-Tg) that express the transgenic ganp gene under immunoglobulin enhancer and promoter control. Ganp-Tg mice showed a high incidence of lymphomagenesis (29.5%) after aging with a non-B/non-T cell surface phenotype having slight CD45R/B220 expression and Ig transcripts of rearranged VH-DH-JH IgH loci. Lymphomas generated in ganp-Tg mice displayed similar pathologic characteristics to mouse reticulum cell neoplasm or Hodgkin lymphoma–like lesions. The VH sequences of individual mice showed that the tumors proliferated from a single clone or oligoclones, as is found in human diffuse large B-cell lymphomas and Hodgkin lymphoma. These results suggest that GANP overexpression is a causative factor in the generation of B lymphomas.

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