The natural history of genetic drivers of chronic lymphocytic leukemia development as early as 16 years prior to diagnosis

Chronic lymphocytic leukemia (CLL) is invariably preceded by monoclonal B-cell lymphocytosis (MBL), a potential CLL precursor state which can be detected in up to 17% in aged individuals. Recently, we described significant B-cell receptor immunoglobulin heavy chain (BCR IGH) gene repertoire skewing and clonotypic evolution up to 22 years before CLL diagnosis. However, pathobiological drivers during the earliest stages of MBL development remain incompletely characterized. In this study, we utilized the EuroClonality-NDC panel to sequence recurrently mutated genes in CLL in 39 peripheral blood samples from 16 CLL patients sampled up to 16 years prior to diagnosis. CLL diagnosis ranged from 5 months to 16 years after first blood sampling. Of 16 CLL patients, 8 (50%) presented with variants of interest in genes recurrently mutated in CLL such as NOTCH1, ATM, SF3B1 and BRAF. ATM variants and the IGLV3-21R110 mutation were present from the early stages of (pre)MBL development, while NOTCH1, SF3B1, XPO1 and BRAF variants arose closer to diagnosis. We additionally detected variants in FAT1 and PLCG2 as early as 10 years prior to CLL diagnosis. Overall, our data shows specific genetic drivers of CLL are associated with early and late stages of CLL development.