CLL pathobiology: from MBL to Richter syndrome. Although the MBL to CLL conundrum is far from solved, a plausible (although speculative) explanation could be that mechanisms that induce clonal expansion, such as ongoing antigenic stimulation through the B-cell receptor together with accessory cells operating within specific micro-environmental niches, trigger the clonal development of MBLs. Over time, the pressure of stimulation may give rise to enhanced proliferation leading to the acquisition of genetic abnormalities, e.g. del(13q), and gene mutations that appear late in the expanding clone, and eventually some MBLs may progress into overt CLL. Since not all cases of MBL have the potential to progress into overt full-blown CLL, the type of micro-environmental stimulation occurring throughout time as well as the occurrence of distinct genomic aberrations may account for such transformation. Progression toward a more malignant disease may be fueled by the presence of specific genetic lesions, e.g. TP53 abnormalities, NOTCH1, which in turn may lead to resistance to therapy and in rare cases, transformation to Richter syndrome.
Haematologica. 2015 January;100(1):7-16.