Proteogenomic subtyping of chronic lymphocytic leukemia identifies subgroups with contrasting clinical outcome and distinct ex-vivo drug response profile – DIA Validation

We have performed a comprehensive proteomic analysis of clinical patient samples of chronic lymphocytic leukemia (CLL) alongside genome-, transcriptome- and ex-vivo drug response profiling. Trisomy 12 and IGHV mutation status had the strongest impact on the proteome and transcriptome; and SF3B1 mutations preferentially affected the proteome. Unsupervised clustering of the proteome data partitioned CLL patients into six protein based subgroups (PG) with contrasting clinical behavior. PG1-4 could be explained by the impact of trisomy 12 and IGHV mutation status on protein abundances and another subgroup (PG6), was enriched for TP53 mutations. In addition we uncovered a new subgroup (PG5) only detectable from the proteome, characterized by low expression of central B-cell receptor proteins, altered splicing, metabolic reprogramming and increased sensitivity to proteasomal inhibition. We further validated the existence of this subgroup by conducting DIA based proteomics of an additional 167 patients. This entry contains the DIA-data for 167 patients used to validate the subgroups identified using HiRIEF-LC-MS/MS (see separate accession: PXD017453) as well as DIA data for 36 of the original discovery cohort. https://www.ebi.ac.uk/pride/archive/projects/PXD028936