Figure 5. A distinct pathway of clonal evolution in MGUS and MM originating from a germinal center B cell undergoing somatic hypermutation.

Striking intraclonal variation (ICV) in patterns of tumor-derived IGHV gene sequence mutations in MM suggest a model in which a germinal center (GC) B cell that has undergone neoplastic Event 1, possibly at the stage of deletional class-switch recombination, re-enters the GC dark zone and is subjected to on-going somatic hypermutation (SHM). It is postulated that such a cell may be a ‘pre-PC’ committed to terminal maturation but able to undergo SHM, which exits the GC to home to the bone marrow to accumulate as MGUS. Subsequent sum of neoplastic Events 2-N in MGUS cells generate malignant MM, which retain the imprint of ICV resulting from the GC cell of origin being exposed to on-going SHM in tumor-derived IGHV genes.