Expression of Mutated IGHV3-23 Genes in Chronic Lymphocytic Leukemia Identifies a Disease Subset with Peculiar Clinical and Biological Features

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. ©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

The miR-17∼92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes

“…12,13 However, little is known regarding the capacity of external stimuli to modulate the expression of specific microRNAs and/or microRNA families in CLL. In this regard, studies by our group have recently demonstrated a close correlation between the expression of a particular BCR (that is, IGHV3-23) with relatively higher levels of two key microRNAs (that is, miR-15a and miR-16-1), 14 indicating that the expression of certain microRNAs could be modulated by BCR signals.…”

“…Additional biological features of CLL cases entering this study, including expression of ZAP-70 and CD38, interphase fluorescence in-situ hybridization for the main chromosomal abnormalities and the experiments for which each sample has been used are listed in Supplementary Table S1. 1,14,15 In all cases, CLL cells were purified by negative selection using anti-CD3, anti-CD14 and anti-CD16 mouse monoclonal antibodies and Dynabeads coated with a pan anti-mouse IgG antibody (Dynal Biotech, Oslo, Norway). 8 The purity of the CLL cells after negative selection was monitored by flow cytometry, and the percentage of CD5 þ /CD19 þ cells exceeded 98% for all the CLL samples from the patients entering the study.…”

“…To identify the putative microRNAs involved in gene deregulation, GEP data were investigated using the open-source applications 'Targets' Reverse Expression' (T-REX), available at http://aqua.unife.it, and 'Gene Set Enrichment Analysis' (GSEA). 14,19 Further details are provided in Supplementary Materials and Methods.…”

Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations

“…[3][4][5][6] Moreover, cases with particular B-cell receptor immunoglobulin (BcR IG; eg, those expressing specific IGHV genes) have been reported to not abide by the M-CLL/U-CLL categorization rule. [7][8][9] A paradigmatic example concerns IGHV3-21 gene usage, which has been correlated with shorter overall survival (OS) independently of SHM status. [10][11][12] Interestingly, more than half of CLL cases utilizing the IGHV3-21 gene display highly similar variable heavy complementarity determining region 3 (VH CDR3) sequences and light-chain gene usage [9][10][11][12][13][14] ; thus, they fulfill the criteria of BcR IG stereotypy, a frequent phenomenon in CLL, occurring in ;30% of patients.…”

Heterogeneous Nuclear Ribonucleoprotein K Supports Vesicular Stomatitis Virus Replication by Regulating Cell Survival and Cellular Gene Expression

“…Our present results demonstrate that TIA1b is inhibitory to VSV replication. Since expression of TIA1 is mediated by many cellular factors including miRNAs (64,65), it would be of interest to examine how hnRNP K regulates or is regulated by these factors, which may provide further understanding of the role of cellular factors involved in VSV replication.…”