Molecular genetics of high-risk chronic lymphocytic leukemia

In an optimized management algorithm of chronic lymphocytic leukemia (CLL), the early identification of high-risk patients, ideally prior to treatment, is a prerequisite for designing strategies tailored at overcoming therapy resistance. TP53 abnormalities play a central role in our current understanding of the poor prognosis of high-risk CLL patients, but fail to explain the molecular basis of 50% of high-risk CLL. Next-generation sequencing studies have revealed several novel genetic alterations in high-risk CLL, including NOTCH1, SF3B1 and BIRC3 mutations. Alterations of these genes occur in 5-10% of CLL at diagnosis, show a prevalence that increases in the more advanced phases of the disease, and confer poor prognosis in consecutive CLL series.