Common progenitor cells in mature B-cell malignancies: Implications for therapy

PURPOSE OF REVIEW: This review summarizes the recent progress in defining the patterns of genetic evolution giving rise to relapse in follicular lymphoma and multiple myeloma, and discusses their implications with respect to 'personalized medicine'. RECENT FINDINGS: High-throughput sequencing studies have uncovered a large degree of clonal heterogeneity within tumors, and found that subclones have a variable contribution to relapse. Recent studies aimed at defining patterns of clonal evolution have revealed that serial tumors in some malignancies share their ancestry in a less evolved common progenitor cell (CPC) that bears only a subset of the mutations that are present in the fully evolved tumors that present clinically. This pattern of 'divergent evolution' means that the majority of 'actionable mutations' in tumor specimens are absent within the progenitors that give rise to relapse. SUMMARY: Follicular lymphoma and multiple myeloma are clinically, biologically and genetically distinct mature B-cell malignancies. However, recent studies have found them to share important similarities in their patterns of genetic evolution. Tumor cells that constitute subclonal populations within these tumors, or between consecutive tumors, share their origins within a genetically less evolved common progenitor cell. This pattern of evolution indicates that current therapies are unable to eradicate these less evolved populations that are at the root of relapse. This suggests that in order to obtain the best results with modern 'targeted therapies' that are directed towards 'actionable mutations', these mutations should be considered within the context of the evolutionary stage at which mutations are acquired, not simply on a presence or absence basis.