Distinctive IGHV gene usage and stereotyped receptors in South American patients with chronic lymphocytic leukemia

Abstract

The IGHV (immunoglobulin heavy-chain variable region) gene mutational status is one of the most important prognostic factors in chronic lymphocytic leukemia (CLL). At present, there is limited information about CLL patients from South American countries. We have evaluated the IGHV mutational status, gene usage and stereotyped BCRs in CLL patients from four South American countries, in a multi-institutional collaborative study. Results were correlated with genomic aberrations and clinical prognostic factors of the disease. Our cohort included 900 unselected CLL patients from Argentina (362), Brazil (358), Uruguay (101) and Venezuela (79). The whole series showed 52.6% M-CLL and 47.4% UM-CLL patients. IGHV3 family was prevalent (42.9%), while IGHV4 and IGHV1 showed the same frequency (24%). IGHV1-69 gene was the most frequently used (12.2%), followed by IGHV4-34 and IGHV3-23. IGHV1-69 was the most frequent rearrangement in Brazilian patients, Uruguayan series showed the highest frequencies of IGHV3-7 and IGHV3-23, and IGHV3-21 was preferentially expressed in Venezuelan cohort. Stereotyped BCRs were present in 14% of cases, mostly associated with an UM state (69%); 66% of them belong to major subsets. In the whole series, subset #4 was the most frequently found, followed by subsets #1 and #2. Subset #1 was the largest in Brazil, subset #2 in Argentina, whereas subset #4 was the most frequently found in Uruguay and Venezuela. IGHV4-34 gene showed a higher proportion of stereotypy in Argentina and Uruguay with significant differences between Brazil and Uruguay (p=0.007). One potential novel subset was found. Association between complex karyotypes, ≥2 FISH alterations, trisomy 12 and 11q22 deletion with UM-IGHV state (p<0.04) was observed. Advanced clinical stage, higher whole blood count and β2microglobulin levels (p<0.03) as well as a short time to first treatment (p=0.0001) were also associated to UM-CLL patients. Our results show interesting differences between CLL patients from different South American countries, reflecting the role of genetic background and environmental factors in CLL pathogenesis in our subcontinent.