Posted: Friday, October 14, 2022
During the 2022 Society of Hematologic Oncology (SOHO) Annual Meeting (Abstract EXABS-176-CLL), Kostas Stamatopoulos, MD, PhD, of the Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece, reflected on the clinical significance of B-cell receptors in chronic lymphocytic leukemia (CLL).
Leukemic B cells of patients with CLL were first reported to express certain IGHV genes. Years later, it was discovered these mutations were not random and made up a significant portion of CLL-carried somatic hypermutations. Moreover, this hypermutation status of these genes was found to directly predict the survival of patients in this subset.
Further investigation showed that a high percentage of CLL cases with B-cell receptor immunoglobulin encoded by IGHV3-21 carried almost identical amino acid sequences within the variable heavy complementary determining region 3. In fact, according to the investigators, a recent study of nearly 30,000 participants revealed that 41% of all cases expressed this stereotyped B-cell receptor immunoglobulin.
This finding poses three hypotheses: Certain subsets demonstrate strikingly enriched genomic aberrations; different subsets can exhibit distinct DNA methylation profiles regardless of hypermutation status; and cell signaling via B-cell receptors can be very different between subsets.
Subset #2 remains the largest stereotyped subset of CLL, with B-cell receptor immunoglobulins that are composed of heavy and light chains encoded by genes IGHV3-21 and the IGLV3-21. This subset has a poor clinical outcome, which is independent of somatic hypermutation status, according to the study authors. Furthermore, classification into subset #2 appears to be its own independent prognostic marker for a shorter time to next treatment and progression-free survival.
In contrast, subset #8 harbors B-cell receptors that are encoded by the genes IGHV4-39/IGKV1(D)-39. Individuals in this subset have a 10-fold higher risk for developing Richter’s transformation than other patients with CLL, which is the highest of any subset. Thus, closer follow-up is recommended for this population.
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