Reading the B-cell receptor immunome in chronic lymphocytic leukemia: revelations and applications

B-Cell receptor (BCR) sequencing has been the force driving many recent advances in chronic lymphocytic leukemia (CLL) research. Here, we discuss the general principles, revelations, and applications of reading the BCR immunome in the context of CLL. First, IGHV mutational status, obtained by measuring the mutational imprint on the IGHV gene of the CLL clonotype, is the cornerstone of CLL risk stratification. Furthermore, the discovery of "BCR-stereotyped" groups of unrelated patients that share not only a highly similar BCR on their leukemic clone, but also certain clinical characteristics has provided insights key to understanding disease ontogeny. Additionally, whereas the BCR repertoire of most CLL patients is characterized by a single dominant rearrangement, next-generation sequencing (NGS) has revealed a rich subclonal landscape in a larger than previously expected proportion of CLL patients. We review the mechanisms underlying these "multiple dominant" cases, including V(D)J-recombination errors, failure of allelic exclusion, intraclonal diversification, and "true" bi- or oligoclonality, and their implications, in detail. Finally, BCR repertoire sequencing can be used for sensitive quantification of minimal residual disease to potentially unprecedented depth. To surmount pitfalls inherent to this approach and develop internationally harmonized protocols, the EuroClonality-NGS Working Group has been established.