Clonal evolution in chronic lymphocytic leukemia: impact of subclonality on disease progression

Abstract

In recent years, next-generation sequencing has unraveled the molecular landscape in chronic lymphocytic leukemia with the discovery of a number of recurrently mutated genes. Mutations in several of these genes, such as NOTCH1, SF3B1 and BIRC3, are linked to a more aggressive disease with early disease progression, short time-to-first-treatment and even chemorefractoriness. Although in its infancy, we have also begun to understand the complex dynamics of subclonal diversity and its impact on disease outcome. From pioneering studies, we know that certain genetic events are found in the majority of chronic lymphocytic leukemia cells and are considered as ‘clonal driver mutations’ (e.g., +12, 13q−), whereas others, present only in a fraction of the tumor, are deemed to be ‘subclonal driver mutations’ for example, TP53 and SF3B1. Over the coming years, we need to gain a deeper insight into the dynamics of this subclonal architecture to understand how, at an individual level, chronic lymphocytic leukemia patients should be followed, which will be particularly relevant as novel targeted therapies begin to emerge.

Keywords:

• chronic lymphocytic leukemia
• clonal evolution
• gene mutations
• genomic aberrations
• next-generation sequencing
• prognosis
• subclonality

Financial & competing interests disclosure

This research was supported by the Swedish Cancer Society, the Swedish Research Council, Uppsala University Hospital and the Lion’s Cancer Research Foundation, Uppsala. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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