2p Gain-Driven REL Overexpression Confers Resistance to BTK Inhibitors in Chronic Lymphocytic Leukemia

Gain of the short arm of chromosome 2 (2p) is a frequent chromosomal abnormality in advanced Chronic Lymphocytic Leukemia (CLL), but how it contributes to CLL pathogenesis and progression is still poorly understood. Using a multiparameter approach that combines scRNA sequencing, cellular biology on primary CLL cells and engineered cell lines, as well as clinical analyses, our data show that 2p gain leads to NF-kB activation through REL overexpression, thereby contributing to BTKi resistance. Overall design: single-cell RNA-seq profiling of five peripheral blood mononuclear cells (PBMC) samples from CLL patients with a gain of the short arm of chromosome 2.