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 ¼ 25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated V H 3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; Po0.01), including mutated cases (6/432; 1.39%; Po0.01) and was exceptional among indolent (1/230, 0.435%; Po0.01), and aggressive B-cell lymphomas (0/105; Po0.01). Three of six V H 3-72 B-CLL cases utilized the same V L V j 4-1 gene. Two V H 3-72 B-CLL cases had highly homologous V H complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized V j 4-1 genes with homologous IgV L CDR3s. An identical threonine to isoleucine change at codon 84 of V H 3-72 framework region 3 (FR3) recurred in four cases of highly stable V H 3-72 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 H 3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.

Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients

“…Other evidence already suggests, however, that additional characteristics of the Ig sequence may substratify clinical outcomes and enhance a prognostic model. For instance, IGHV3-21 and IGHV3-72 usage provides clinically important prognostic information independent of the IGHV gene mutation status (13)(14)(15)(16)(17)(18). With that in mind, we evaluated an exclusively UM low/intermediate Rai risk patient cohort to determine whether specific molecular features of the IGHD and IGHJ genes predicted prognosis.…”

“…For example, patients expressing the IGHV3-21 gene have a poor prognosis regardless of mutation status (13)(14)(15)(16). In contrast, patients expressing the IGHV3-72 gene have a favorable immunophenotypic profile (CD38- and ZAP-70-negative) and consistently exhibit a stable and indolent disease course (17,18).…”

“…More extensive analysis of the molecular structure of the BCR in leukemic B cells has also suggested that subgroups of B-CLL patients express strikingly similar BCRs with respect to IGHD and IGHJ genes and, thus, similar HCDR3s (14)(15)(16)(17)(19)(20)(21)(22)(23)(24). For exam-ple, the IGHV1-69 gene appears to be the most frequently expressed IGHV gene in B-CLL, usually in an UM form, and has been reported to be preferentially used with the IGHD3-3 gene, IGHJ6 gene, and the IGHV1-69 51p1-like allele (25)(26)(27).…”

CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study

“…Recently, several publications reported the prognostic significance of specific immunoglobulin variable heavy chain (IGHV) gene features in CLL. [10][11][12][13][14][15] However, since IGHV gene sequencing remains a demanding technique, many studies focused on the identification of alternative markers with similar prognostic value the expression of which is easier to investigate, such as CD38 and T-cell specific zeta-associated protein-70 (ZAP-70). [16][17][18][19][20][21][22] Literature data confirm that leukemic CLL cells bear the surface membrane phenotype of activated and antigenexperienced B lymphocytes with the overexpression of the activation markers CD23, CD25, CD69 and CD71.…”

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

“…Currently, the most widely used biomarkers are cytogenetics, immunoglobulin heavy-chain variable gene mutation status (IGHV-MS) and expression of ZAP70 and CD38. [4][5][6][7][8][9][10][11][12][13][14] Despite the established prognostic value of these biomarkers, a stratification according to these parameters does not fully explain the heterogeneity of CLL. In addition, scant information is available on independent predictors of some critical events in CLL, such as clinicopathological transformation to aggressive lymphoma, also known as Richter's syndrome (RS).…”