🇬🇧 Genomics of CLL: from driver discovery to functional interrogation

Abstract

Despite the flood of knowledge gained from large-scale sequencing studies across cancers, we still know relatively little about the functional impact of the discovered putative drivers identified through analyses of statistical frequency.
Chronic lymphocytic leukemia (CLL) is an advantageous setting in which to address this challenge because of its low overall mutation rate and relatively high ratio of driver to passenger mutations, providing an opportunity to focus on a limited set of alterations with high likelihood of oncogenic impact. Better understanding of how these candidate events mechanistically contribute to CLL generation will possibly reveal the steps by which CLL develops and the potential vulnerabilities by which disease subtypes can be rationally targeted. Functional studies in primary CLL-B cells have long faced many obstacles due to rare cell lines that are faithful to the human disease, and the difficulties in efficiently manipulating human B cells using conventional genetic approaches. Mouse models provide an established path to undertake mechanistic studies. Several transformative advances in genetic engineering have enabled an improved ability to assess the in vivo effects of candidate drivers, and include the ability to generate conditional knock-in of mutations into endogenous gene loci. Indeed, we previously reported the use of this approach to study the B- cell restricted combination of Atm deletion and heterozygous Sf3b1 mutation, in which we observed the generation of lowly-penetrant CLL (Yin Cancer Cell 2019), and the modeling of the Ikzf3 mutation, which instead leads to highly-penetrant disease, as a sole lesion (Lazarian Cancer Cell 2021). Building on the prior studies of mut-Sf3b1/Atm and mut-Ikzf3 mice, we have recently generated new likely gain-of-function mutation models to evaluate the leukemia-initiating and transformation potential of combinations of traits. We thus aim to formulate an overall picture of the cardinal steps essential to transform a normal B cell to CLL.