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

February 13, 2010

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 ti, D Rossi, MI Del Principe, F Luciano, E Sozzi, I Cattarossi,

A Zucchetto, FM Rossi, P Bulian, E Zucca, MS Nicoloso, M Degan, R Marasca, DG

Efremov, G Del Poeta, G Gaidano, and V Gattei

Clin. Cancer Res., January 15, 2010; 16(2): 620-8.

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento

Oncologico, I.R.C.C.S., Aviano (PN), Italy.

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.

PMID: 20068100

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