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. Clin Cancer Res; 16(2); 620–8

Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features / Bomben, R; Dal Bo, M; Benedetti, D; Capello, D; Forconi, F; Marconi, D; Bertoni, F; Maffei, Rossana; Laurenti, L; Rossi, D; Del Principe, Mi; Luciano, F; Sozzi, E; Cattarossi, I; Zucchetto, A; Rossi, Fm; Bulian, P; Zucca, E; Nicoloso, Ms; Degan, M; Marasca, Roberto; Efremov, Dg; Del Poeta, G; Gaidano, G; Gattei, V.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - 15:(2010), pp. 620-628. [10.1158/1078-0432.CCR-09-1638]

Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features.

MAFFEI, Rossana;MARASCA, Roberto;
2010

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. Clin Cancer Res; 16(2); 620–8
15
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Expression of mutated IGHV3-23 genes in chronic lymphocytic leukemia identifies a disease subset with peculiar clinical and biological features / Bomben, R; Dal Bo, M; Benedetti, D; Capello, D; Forconi, F; Marconi, D; Bertoni, F; Maffei, Rossana; Laurenti, L; Rossi, D; Del Principe, Mi; Luciano, F; Sozzi, E; Cattarossi, I; Zucchetto, A; Rossi, Fm; Bulian, P; Zucca, E; Nicoloso, Ms; Degan, M; Marasca, Roberto; Efremov, Dg; Del Poeta, G; Gaidano, G; Gattei, V.. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - STAMPA. - 15:(2010), pp. 620-628. [10.1158/1078-0432.CCR-09-1638]
Bomben, R; Dal Bo, M; Benedetti, D; Capello, D; Forconi, F; Marconi, D; Bertoni, F; Maffei, Rossana; Laurenti, L; Rossi, D; Del Principe, Mi; Luciano, F; Sozzi, E; Cattarossi, I; Zucchetto, A; Rossi, Fm; Bulian, P; Zucca, E; Nicoloso, Ms; Degan, M; Marasca, Roberto; Efremov, Dg; Del Poeta, G; Gaidano, G; Gattei, V.
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