Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features
R. Bomben, M. Dal-Bo, D. Benedetti, D. Capello, F. Forconi, D. Marconi, F. Bertoni, R. Maffei, L. Laurenti, D. Rossi, M. I. Del Principe, F. Luciano
(+13 others)
2010
Clinical Cancer Research
Purpose: B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease whose outcome can be foreseen by investigating the mutational status of immunoglobulin heavy chain variable (IGHV) genes. Moreover, a different prognosis was reported for CLL expressing specific IGHV genes in the context or not of stereotyped B-cell receptors. Here we investigated novel associations between usage of specific IGHV genes and clinical features in CLL. Experimental Design: Among 1,426
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... ic IG-rearrangements, stereotyped B-cell receptor clusters never utilized the IGHV3-23 gene. Given this notion, this study was aimed at characterizing the IGHV3-23 gene in CLL, and identifying the properties of IGHV3-23-expressing CLL. Results: IGHV3-23 was the second most frequently used (134 of 1,426) and usually mutated (M; 109 of 134) IGHV gene in our CLL series. In the vast majority of M IGHV3-23 sequences, the configuration of the 13 amino acids involved in superantigen recognition was consistent with superantigen binding. Clinically, M IGHV3-23 CLL had shorter time-to-treatment than other M non-IGHV3-23 CLL, and multivariate analyses selected IGHV3-23 gene usage, Rai staging, and chromosomal abnormalities as independent prognosticators for M CLL. Compared with M non-IGHV3-23 CLL, the gene expression profile of M IGHV3-23 CLL was deprived in genes, including the growth/tumor suppressor genes PDCD4, TIA1, and RASSF5, whose downregulation is under control of miR-15a and miR-16-1. Accordingly, relatively higher levels of miR-15a and miR-16-1 were found in M IGHV3-23 compared with M non-IGHV3-23 CLL. Conclusions: Altogether, expression of the IGHV3-23 gene characterizes a CLL subset with distinct clinical and biological features. Clin Cancer Res; 16(2); 620-8. ©2010 AACR. Chronic lymphocytic leukemia (CLL) is a heterogeneous disease whose clinical course can be foreseen by the presence of mutated (M) or unmutated (UM) immunoglobulin heavy chain variable (IGHV) genes (1). Although CLL with UM IGHV genes usually has a worse prognosis, great heterogeneity is still documented in the context of CLL subgroups expressing either UM or M IGHV genes (1). Analyses of IGHV gene usage has revealed a biased repertoire occurring in CLL versus normal B cells, and in UM versus M CLL (1, 2). Moreover, a discrete fraction of CLL expresses stereotyped combinations of IGHV genes, complementarity-determining region-3 (HCDR3), and IGV light chains (3-7). These observations, coupled with an IGHV mutation profile often consistent with antigen-driven
doi:10.1158/1078-0432.ccr-09-1638
pmid:20068100
fatcat:eod5ipr5nzbqlit3ws62zv3yuu
