Bomben, Riccardo, Dal-Bo, Michele, Benedetti, Dania, Capello, Daniela, Forconi, Francesco, Marconi, Daniela, Bertoni, Francesco, Maffei, Rossana, Laurenti, Luca, Rossi, Davide, Del Principe, Maria Ilaria, Luciano, Fabrizio, Sozzi, Elisa, Cattarossi, Ilaria, Zucchetto, Antonella, Rossi, Francesca Maria, Bulian, Pietro, Zucca, Emanuele, Nicoloso, Milena S., Degan, Massimo, Marasca, Roberto, Efremov, Dimitar G., Del Poeta, Giovanni, Gaidano, Gianluca and Gattei, Valter (2010) Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features. Clinical Cancer Research, 16 (2), 620-628. (doi:10.1158/1078-0432.CCR-09-1638). (PMID:20068100)
Abstract
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 CLL-specific 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.
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