Why Is the Immunoglobulin Heavy Chain Gene Mutation Status a Prognostic Indicator in Chronic Lymphocytic Leukemia?

Abstract

The immunoglobulin heavy chain gene (IgHV) mutation status correlates with the clinical outcome of patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy. Why the survival rate of patients with unmutated IgHV is worse than that of patients with mutated IgHV is unknown. CLL cells with unmutated IgHV were thought to originate from naïve B lymphocytes, whereas CLL cells with mutated IgHV were thought to arise from B cells that have undergone somatic hypermutation (SHM). Cell surface protein expression profile and gene expression studies showing that all CLL cells, regardless of their IgHV mutation status, are of postgerminal center origin, negated this hypothesis. We hereby propose that all CLL cells undergo SHM and their proliferation rate determines their IgHV mutation status. DNA breaks, accumulated during SHM, are restored by various DNA repair mechanisms. In rapidly dividing cells DNA breaks are repaired by the efficient high-fidelity homology-directed DNA repair apparatus, whereas in slowly dividing cells they are repaired by the inefficient low-fidelity nonhomology end-joining repair mechanism. Accordingly, a low IgHV mutation rate is found in rapidly dividing cells whereas a high mutation rate is typically found in slowly dividing cells. Thus, the proliferation rate of CLL cells determines the IgHV mutation status and patients’ clinical outcome.

Identification of a novel tRNA‐derived RNA fragment exhibiting high prognostic potential in chronic lymphocytic leukemia

“…Similar results were observed for patients expressing CD38, normal or abnormal LDH serum concentration. Unmutated IGHV region is linked to higher proliferation of CLL cells, and CD38 expression is associated with aggressive disease . Nonelevated LDH serum concentration is associated with higher survival rates than the elevated one .…”

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…According to the IGHV mutation status, patients can be divided into mutated CLL (M-CLL) patients and unmutated CLL (U-CLL) patients. Unmutated IGHV status, relating to shorter LDT and CD38 overexpression, is associated with a more aggressive course of CLL and predicts shorter TTFT in treatment-naïve patients, while M-CLL patients have better outcomes [ 44 – 47 ]. However, the correlation between U-CLL and CD38 expression was not found in another study [ 48 ].…”

Prognostic and Predictive Molecular Biomarkers in Chronic Lymphocytic Leukemia

“…CLL cases with unmutated IGHV are thought to have increased B-cell receptor (BCR) signaling and increased malignant cell proliferation. 37,38 Laboratory determination of IGHV mutation status involves mainly sequencing of the variable region of the Ig heavy chain and aligning the resulting sequences with the germ-line sequences, where !98% homology or 2% mutation to the germ-line IGV sequence is interpreted as unmutated and >2% mutation and <98% homology is considered mutated. A new category of borderline cases is recently defined as having 97.0% to 97.9% homology.…”