Catherine J. Wu
Associate Professor, Department of Medicine, Harvard Medical School
Associate Physician, Medical Oncology, Dana-Farber Cancer Institute
Precise Dissection of Genetic and Transcriptional Heterogeneity in Chronic Lymphocytic Leukemia by Single Cell Analysis
Intratumoral genetic heterogeneity is the basis of tumor cell plasticity and has been characterized across cancers by genome-wide studies of bulk tumors through the tracking of somatic tumor mutations, including in chronic lymphocytic leukemia (CLL). To more accurately detect subclones, define phylogenetic relationships and to directly uncover genotype-phenotype relationships, we have developed versatile approaches for targeted mutation detection from hundreds of single cell DNA and RNA isolated from CLL samples, previously well-characterized by bulk whole-exome and transcriptome sequencing. Our targeted single-cell profiling approach enabled simultaneous interrogation of somatic point mutations and chromosomal alterations, clearly resolving phylogenic relationships and further could directly link the presence of somatic mutations with disrupted gene expression, including the presence of the mutated splicing factor SF3B1 and the expression of splice variants; and of resistance mutations with expression changes in driver pathways. Our study reveals the potential for single cell RNA-based analysis to directly uncover the effects of driver mutations on the leukemia cell phenotype.
