Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> Among 1,426 CLL-specific IG-rearrangements, stereotyped B-cell receptor clusters never utilized the <i>IGHV3-23</i> gene. Given this notion, this study was aimed at characterizing the <i>IGHV3-23</i> gene in CLL, and identifying the properties of <i>IGHV3-23</i>–expressing CLL.</p><p><b>Results:</b> <i>IGHV3-23</i> 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 <i>IGHV3-23</i> 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 <i>IGHV3-23</i> 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 <i>PDCD4, TIA1</i>, and <i>RASSF5</i>, whose downregulation is under control of <i>miR-15a</i> and <i>miR-16-1</i>. Accordingly, relatively higher levels of <i>miR-15a</i> and <i>miR-16-1</i> were found in M IGHV3-23 compared with M non–IGHV3-23 CLL.</p><p><b>Conclusions:</b> Altogether, expression of the <i>IGHV3-23</i> gene characterizes a CLL subset with distinct clinical and biological features. Clin Cancer Res; 16(2); 620–8</p></div>

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