The Rho family of small GTPases including Rho, Rac, Cdc42 has been well characterized as molecular switches to transduce signals from plasma membrane to the downstream effectors. RhoH, a member of the Rho family, is specifically expressed in hematopoietic cells, especially in T and B lymphocytes, and has been reported to downregulate Rac and LFA-1. As RhoH is GTPase deficient and constitutively active, GTP-bound form, the activity of RhoH is directly related to the level of expression. Aberrant somatic hypermutation (SHM) of RhoH gene has been reported in 43% of Diffuse Large B cell Lymphoma (DLBCL) patients (

Pasqualucci L et.al., Nature. 2001;412:341–346
). Although several studies demonstrated the SHM of DLBCL and other lymphoid malignancy, few of the previous reports investigated the clinical significance of SHM. To definitively resolve this issue, we have screened for SHM of RhoH gene in the lymph node samples from 100 previously untreated DLBCL cases. These patients were diagnosed and treated at Nagoya University hospital since 1987 to 2002. Informed consent was obtained from all patients. Samples from 12 cases of reactive lymphadenopathy were also screened for negative control. Intron 1 of RhoH gene was amplified and screened by a denaturing HPLC technique (Transgenomic WAVE_). Mutant samples were confirmed by direct sequencing. We found 78 mutations (76 point mutations, 2 insertions) unique to individual tumor DNAs in 36 of 100 DLBCL cases (36%) in RhoH. Overall, 73 out of 78 were novel SHM, and five were same mutations as previously reported (
Pasqualucci L et.al., Nature. 2001;412:341–346
). The number of mutation in one patient ranged from one to six, and 20 patients had more than one mutations. These mutations were distributed in a region throughout the first 1.6 kb of the RhoH gene. The presence of aberrant SHM in RhoH gene impacted neither on overall survival nor disease free survival (p=0.36 and 0.69, respectively). The absence of aberrant SHM correlated with advanced stage (stage III and IV, p<0.05). Taken together, our study demonstrated that although the SHM might contribute the lymphomagenesis through regulation of RhoH gene expression, it has less impacts on survival of DLBCL patients.

Topics:
diffuse large b-cell lymphoma, cdc42 gtp-binding protein, guanosine triphosphate phosphohydrolases, high pressure liquid chromatography procedure, leukemogenesis, lymphadenopathy, lymphocyte function-associated antigen-1, lymphoid neoplasm, malignant, monomeric gtp-binding proteins, neoplasms

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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