Deletion of Rhoh Accelerates Development of Diffuse Large B Cell Lymphoma in Bcl-6 Transgenic Mouse Model

Abstract Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy of mature B lymphocytes, accounting for 30%-40% of cases of non-Hodgkin's lymphoma. DLBCL has been classified by gene expression profiling into three subtypes GC-B-cell like (GCB)-DLBCL, activated B-cell like (ABC)-DLBCL and primary mediastinal B cell lymphoma (PMBL) or by immunohistological analysis into two subtypes, GCB-DLBCL and non-GCB- DLBCL. Rho H, a hematopoietic-specific Rho GTPase is required for CD3-zeta phosphorylation and recruitment of the protein tyrosine kinases Zap70 and Lck to the cellular membrane and immunologic synapse (Gu et al. Nat Immunol. 2006). Therefore, Rho H deficient (Rhoh-/-) mice exhibit T-cell deficiency due to impaired T-cell receptor-mediated selection and maturation of thymocytes. RHOH was first identified as a hypermutable gene and translocation partner in human B cell malignancies (Dallery E, et al . Oncogene. 1995) and RHOH mutations have been reported in 35 of 100 DLBCL cases (Hiraga J, et al. Leukemia. 2007). However, the effect of RHOH mutations and translocations on RHOH expression and the biology of lymphoma are completely unknown.We crossed Rhoh-/- and the DLBCL mouse model Iµ-HABcl-6 transgenic mouse (Cattoretti G, et al. Cancer Cell. 2005) to generate Rhoh-/- ;Bcl-6Tg and RhohWT;Bcl-6Tg mouse, and compared outcomes of these groups. Rhoh-/-; Bcl-6Tg mice developed severe splenomegaly and succumbed to disease more quickly compared with RhohWT; Bcl-6Tg mice (Figure1, Log-rank test p Download : Download high-res image (86KB) Download : Download full-size image Figure 1 . Disclosures No relevant conflicts of interest to declare.