Understanding CLL pathogenesis
A major challenge in the treatment of chronic lymphocytic leukemia (CLL) is the highly variable clinical outcome of patients with this disease, ranging from indolent disease kinetics to a rapidly fatal course despite aggressive therapy. While some prognostic markers for CLL have been established, they are far from reliable. However, the advent of next-generation sequencing technologies now enables the systematic identification of genetic alterations underlying malignancy.
We recently sequenced the whole-genomes and whole-exomes of 91 CLL samples with matched germline DNA and identified 9 recurrently mutated genes and 6 pathways involved in CLL pathogenesis. A striking finding from this study was the high frequency of mutations in SF3B1, part of the catalytic core of the spliceosome. 15% SF3B1 mutations is localized to a single region of the gene (with unknown function) with 50% being identical K700E mutations. SF3B1-K700E was also identified as a recurring mutation in myelodysplasia2. In short, mutations in SF3B1 are positively selected in CLL, alter splicing patterns, and represent a novel oncogenic mechanism in hematologic malignancies.
We are interested in dissecting the functions of SF3B1 mutation in the pathogenesis of CLL using comprehensive approaches including functional pathway analysis, RNA-Seq, mouse model. We aim to transform our understanding of disease and identify a novel mechanism that can be targeted for treatment of a clinically progressive subgroup for which effective therapies are presently unavailable.