Clonal evolution explains unpredictable leukemia disease course

By Lynda Williams, Senior medwireNews Reporter

Scientists have revealed the complicated clonal evolution of chronic lymphocytic leukemia (CLL), giving insight into the variation in disease course and its response to treatment.

Gad Getz (Broad Institute, Cambridge, Massachusetts, USA) and team used whole-exome sequencing to examine subclonal mutations in 149 CLL patients.

Analysis revealed how CLL develops over time, after the accumulation of cell events leading to a clonal mutation. The founding CLL clonal mutation in a single cell is driven by mutations such as (del(13q), MYD88, and trisomy 12 that recur across patients; these have previously been suggested to drive CLL and B cell malignancies.

This is followed by a third phase of disease progression, where subclonal mutations expand as a result of intrinsic factors, like proliferation or apoptosis, as well as interclonal competition, CLL treatment, and other outside pressures. These subclonal mutations involve well known cancer genes, such as TP53 and RAS.

When the researchers looked at CLL samples from 18 patients at two different time points, they found that clonal evolution occurred in 10 of the 12 patients treated with chemotherapy, with driver mutations in subclones that expanded over time.

Such mutations were shown to confer a significantly increased risk for rapid disease progression, Getz et al note. By contrast, just one of the six patients who not receive chemotherapy showed such subclonal mutations.

"It has been long recognized that relapsed disease responds increasingly less well to therapy over time," the researchers write in Cell.

"We now show an association between increased clinical aggressiveness and genetic evolution, which has therapeutic implications."

The team suggests that assessment of pretreatment subclonal driver mutations could be used to predict the genetic composition of CLL on relapse and potentially guide treatment selection to avoid expansion of "highly fit" subclones.

The researchers add: "The potential hastening of the evolutionary process with treatment provides a mechanistic justification for the empirical practice of 'watch and wait' as the CLL treatment paradigm. The detection of driver mutations in subclones (a testimony to an active evolutionary process) may thus provide a prognostic approach in CLL, which can now be rigorously tested in larger clinical trials."

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