Single-Cell Multi-Omics Reveals Distinct Paths to Survival of Admixed BTKC481Mutant Vs. Wild-Type Cells in Clinically Progressing Chronic Lymphocytic Leukemia

Mutations in the kinase binding domain of BTK at position C481 are associated with resistance to BTK inhibitor (BTKi) therapy in chronic lymphocytic leukemia (CLL). Nearly half of patients manifesting clinical progression with these alterations exhibit a subclonal burden of resistance. Intriguingly, measured BTKC481variant allelic fractions (VAF) are commonly lower than 10% [Ahn et al,Blood 2017]. This raises the important question of how BTKC481-mutated (MUT) and wildtype (WT) cells differ in their response to therapeutic challenge, and how low-burden MUT subclones facilitate escape from therapy.