The VH3-21 Gene Status Correlates with Elevated β2-Microglobulin Serum Levels and Shorter Overall Survival of Patients with Chronic Lymphocytic Leukemia.

Introduction: The prognostic role of immunoglobulin variable heavy chain (IgVH) region somatic hypermutation status in B-cell chronic lymphocytic leukemia (B-CLL) is now well established. However, an overrepresentation of the VH3-21 gene segment has been recently reported to influence clinical course of B-CLL regardless of the IgVH mutational status in different geographic populations. It might suggest the role of a common antigen epitope in the pathogenesis of some B-CLL cases.

Aims: We therefore investigated the frequency of the VH3-21 gene usage in IgVH rearrangements in Polish population of B-CLL patients, and assessed whether it might influence B-CLL clinical characteristics and prognosis.

Patients and Methods: The study comprised of 97 B-CLL patients treated at the Department of Hematology, Medical University of Lodz in Poland. Peripheral blood mononuclear cells were separated on Ficoll and DNA was isolated using column method. The monoclonal population of lymphocytes with VH3-21-JH rearrangement was tested using framework 3 region primer and consensus JH primer described by Davies et al. (Leukemia 2004, 18: 872). The PCR reactions were followed with heteroduplex analysis of PCR products and separation in polyacrylamide gel. The positive VH3-21-JH samples were also confirmed by sequencing.

Results: The frequency of the VH3-21 gene segment in VH-JH rearangements in B-CLL patients reached 9% in Polish population. Beyond an elevated β2-microglobulin serum levels (p=0.03, Mann-Whitney test), no association were found between the VH3-21 gene status and clinical characteristics including CD38 expression at diagnosis The mortality rate was significantly higher in patients carrying VH3-21 (p=0.03, χ2 test), and majority of deaths were related to CLL. With a median follow-up of the surviving patients of 55,5 months (range 2–209 months), the subgroup of patients with the VH3-21 had significantly shorter overall survival (p=0.025, log-rank test). However, this genetic marker was not associated with freedom from progression survival.

Conclusions: We conclude that the frequency of the VH3-21 gene segment in VH-JH rearrangements in Polish population is similar to those previously published for British and Belgian populations and seems to be lower than in Mediterranean area populations (