The Proteome Landscape of Chronic Lymphocytic Leukemia (CLL)

Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are only partially known. This is in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL samples with data-independent acquisition mass spectrometry (DIA-MS) and integrated the results with genomic, transcriptomic, functional data and clinical outcome. We found trisomy 12 and IGHV to be major determinants of proteome variation in CLL (1055 and 542 differential proteins FDR of 5%). Trisomy 12 was associated with limited protein abundance buffering. Protein complex analyses detected functional units involved in BCR/PI3K/AKT signaling in CLL with trisomy 12. We associated protein expression with response to anticancer drugs, and STAT2 protein expression emerged as a biomarker for the prediction of response to kinase inhibitors including BTK and MEK inhibitors. STAT2 protein levels were determined by gene dosage (trisomy 12), stabilization in a protein complex and linked to interferon signaling in CLL. This study highlights the emerging importance of protein abundance profiling in CLL biology.