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


METHODS
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.
Bomben
Riccardo
R
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy.
Dal-Bo
Michele
M
Benedetti
Dania
D
Capello
Daniela
D
Forconi
Francesco
F
Marconi
Daniela
D
Bertoni
Francesco
F
Maffei
Rossana
R
Laurenti
Luca
L
Rossi
Davide
D
Del Principe
Maria Ilaria
MI
Luciano
Fabrizio
F
Sozzi
Elisa
E
Cattarossi
Ilaria
I
Zucchetto
Antonella
A
Rossi
Francesca Maria
FM
Bulian
Pietro
P
Zucca
Emanuele
E
Nicoloso
Milena S
MS
Degan
Massimo
M
Marasca
Roberto
R
Efremov
Dimitar G
DG
Del Poeta
Giovanni
G
Gaidano
Gianluca
G
Gattei
Valter
V
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003937:Diagnosis, Differential; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement / Q000502:physiology; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D009367:Neoplasm Staging; D011379:Prognosis
C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D050505:Mutant Proteins