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Abstract
IGHV4-34 is the most frequently used gene in patients with mutated (M) chronic lymphocytic leukemia (CLL). A significant proportion of cases with mutated IGHV4-34 is assigned to different stereotyped subsets, defined by distinctive quasi-identical BCRs (B-cell receptors). We analyzed the mutational profile of patients with CLL expressing IGHV4-34 in order to refine the molecular characterization of our cohort. Results were correlated with cytogenetic and FISH data. A total of 946 patients from Argentina (393), Brazil (358), Uruguay (116) and Venezuela (79) (558 men; mean age: 65.6 years) were evaluated. The study was approved by the Institutional Ethics Committees.
All individuals provided their informed consent.
A total of 964 productive rearrangements were obtained (15 cases carried two rearrangements and 1 case, three). Of them, 125 (13%) expressed the IGHV4-34 gene, 21 (16.8%) exhibited unmutated (UM) IGHV (≥98% germline identity; GI), while 104 (86.4%) belonged to the M subgroup (<98 GI).
Twenty one IGHV4-34 M gene rearrangements belonged to subset #4, 5 to subset #16 and 1 to subset
#201. Fragments JH6, DH2 and DH5 were predominant in stereotyped CLL while JH4, DH2 and DH3 in non-stereotyped cases. The distribution of remplacement/silent (R/S) mutations showed higher R/S ratios within VH CDR2 and VH FR2 in stereotyped subset #4, in VH CDR2 in subset #16 while VH FR3 was predominant in non-stereotyped rearrangements.
Absence of codon 36 (G36D) mutation in subset #16, of S64I in subsets #4 and #16, high frequency of E55Q in subset#16 and low frequency of P45S in the heterogeneous group were found.
Cytogenetic analysis showed that all patients included in homology subsets had normal karyotypes, compared to 50% in the heterogeneous cases. These findings suggest a particular history of antigen exposure and/or immune response in these patients, and indicate the importance of continuing these studies to get a better molecular delineation of patients with CLL.
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