Deciphering the molecular landscape in chronic lymphocytic leukemia: time frame of disease evolution

Abstract

Dramatic advances in next generation sequencing technologies have provided a novel opportunity to understand the molecular genetics of chronic lymphocytic leukemia through the comprehensive detection of genetic lesions. While progress is being made in elucidating the clinical significance of recurrently mutated genes, layers of complexity have been added to our understanding of chronic lymphocytic leukemia pathogenesis in the guise of the molecular evolution and (sub)clonal architecture of the disease. As we prepare for an era of tailored therapy, we need to appreciate not only the effect mutations have on drug response but also the impact subclones containing specific mutations have at initial presentation, during therapy and upon relapse. Therefore, although the wealth of emerging genetic data has great potential in helping us devise strategies to improve the therapy and prognosis of patients, focused efforts will be required to follow disease evolution, particularly in the context of novel therapies, in order to translate this knowledge into clinical settings.

Figure 1.

Association between recurrent gene mutations and other genetic/immunogenetic features in CLL. Distinct patterns of associations between recurrent mutations and other molecular features have been evidenced in CLL, suggesting different pathways for clonal evolution. For example, NOTCH1 mutations exhibit a strong positive association to trisomy 12 while mutations within SF3B1 often co-occur with del(11q). Although specific patterns of co-occurrence and mutual exclusivity between novel recurrent mutations have been reported, new associations may emerge as larger cohorts are studied.

Figure 2.

Clonal evolution in CLL. Potential routes by which clonal evolution may proceed following therapy. (A) Therapy has little effect on the major clone while minor subclones begin to expand possibly through the acquisition of new genomic lesions. (B) Therapy is effective in eradicating the major clone. However, minor subclones continue to proliferate with the potential to eventually become the dominant clone. w&w; watch and wait.

Figure 3.

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.