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The Protein Landscape of Chronic Lymphocytic Leukemia (CLL)


Abstract

Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry (DIA-MS) and integrated the results with genomic, transcriptomic, ex vivo drug response and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X, and MED12 to influence protein expression (FDR < 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal component analysis (1055 and 542 differentially expressed proteins, FDR=5%). Gene set enrichment analyses of CLL with trisomy 12 implicated BCR/PI3K/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors including BTK and MEK inhibitors. STAT2 was upregulated in U-CLL, trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a non-redundant layer of information in tumor biology, and provides a protein expression reference map for CLL.

Abstract

Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry (DIA-MS) and integrated the results with genomic, transcriptomic, ex vivo drug response and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X, and MED12 to influence protein expression (FDR < 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal component analysis (1055 and 542 differentially expressed proteins, FDR=5%). Gene set enrichment analyses of CLL with trisomy 12 implicated BCR/PI3K/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors including BTK and MEK inhibitors. STAT2 was upregulated in U-CLL, trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a non-redundant layer of information in tumor biology, and provides a protein expression reference map for CLL.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Oncology and Hematology
04 Faculty of Medicine > Functional Genomics Center Zurich
04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:16 December 2021
Deposited On:14 Oct 2021 10:21
Last Modified:18 Mar 2024 04:44
Publisher:American Society of Hematology
ISSN:0006-4971
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/blood.2020009741
PubMed ID:34189564
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