Long-Read Single-Cell RNA Sequencing Enables Cell Genotyping to Refine Subclone Detection in Chronic Lymphocytic Leukemia

Bruton's tyrosine kinase (BTK) inhibitors are effective treatments for chronic lymphocytic leukemia (CLL) due to BTK’s role in B-cell survival and proliferation. Though effective, resistance occurs most commonly due to a BTKC481S mutation that inhibits drug binding. Here, we sought to understand the impact of co-occurring BTK resistance mutations with known CLL driver mutations and the differential transcriptomic behavior of BTK-resistant CLL subclones in six patients who acquired BTKC481S mutations. We utilize MAS-seq, a long-read scRNAseq technology, to increase transcript coverage and expand the set of mutations that can be used to link cells to tumor subclones.