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

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 unmutatedIgHV is worse than that of patients with mutatedIgHV is unknown. CLL cells with unmutated IgHV were thought to originate from na ïve B lymphocytes, whereas CLL cells with mutatedIgHV 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 theirIgHV mutation status, are of postgerminal center origin, negated this hypothesis. We hereby propose that all CLL cells undergo SHM and their proliferation rate determines theirIgHV 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 lowIgHV 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 theIgHV mutation status and patients ’ clinical outcome.Acta Haematol 2018;140:51 –54
Source: Acta Haematologica - Category: Hematology Source Type: research