A recent multi-omics analysis identified multiple chronic lymphocytic leukemia (CLL) subgroups, including a group characterized by poor survival and high proliferative capacity.
Sophie A Herbst, PhD, of the University of Heidelberg, and colleagues conducted the research and published their findings in Nature Communications.
Dr. Herbst and colleagues conducted the research because “cancer heterogeneity at the proteome level may explain differences in therapy response and prognosis beyond the currently established genomic and transcriptomic-based diagnostics.” However, the “relevance of proteomics for disease classifications remains to be established in clinically heterogeneous cancer entities” such as CLL, they wrote.
The study’s authors characterized the proteome and transcriptome of CLL and conducted genetic and ex-vivo drug response profiling in a clinically annotated CLL discovery cohort that included 68 patients. Unsupervised clustering of the proteome data revealed six subgroups of CLL, five of which were associated with genetic features and one of which was only detectable at the proteome level.
The subgroup that was only detectable at the proteome level was “characterized by accelerated disease progression, high spliceosomal protein abundances associated with aberrant splicing, and low B-cell receptor signaling protein abundances,” according to Dr. Herbst and colleagues. The researchers classified this subgroup, which comprised around 20% of the discovery cohort, as altered spliceosome, low B-cell receptor signaling proteins (ASB)-CLL.
ASB-CLL is “characterized by a high proliferative capacity and poor overall survival,” but the inferior overall survival in ASB-CLL was “independent of conventional risk factors such as TP53 aberrations and IGHV mutation status,” Dr. Herbst and colleagues wrote.
The researchers also developed classifiers to identify ASB-CLL “based on its characteristic proteome or splicing signature” in two independent cohorts of 165 and 169 patients, respectively, they wrote. The data from those cohorts confirmed ASB-CLL comprises approximately 20% of all CLL cases.
“Our integrative multi-omics analysis of CLL provides a comprehensive overview of the interplay between genetic alterations, the transcriptome, and the proteome, along with functional consequences for drug response and clinical outcome,” Dr. Herbst and colleagues concluded. “The detailed analysis of our dataset improves our understanding of the biological heterogeneity of CLL and provides molecular phenotype-based subtypes that will improve patient stratification and personalized treatments.”
The comprehensive data set from the study is available at https://www.dietrichlab.de/CLL_Proteomics/.
Herbst SA, Vesterlund M, Helmboldt AJ, et al. Proteogenomics refines the molecular classification of chronic lymphocytic leukemia. Nat Commun. 2022;13(1):6226.