Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia

Abstract

Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (V_H) and light (V_L) chain gene usage in highly stable and indolent B-CLL (n=25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated V_H3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; PPPPH3-72 B-CLL cases utilized the same V_L V4-1 gene. Two V_H3-72 B-CLL cases had highly homologous V_H complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized V4-1 genes with homologous IgV_L CDR3s. An identical threonine to isoleucine change at codon 84 of V_H3-72 framework region 3 (FR3) recurred in four cases of highly stable V_H3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by V_H3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.