Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas

Identification of biomarkers and therapeutic targets is a critical goal of precision medicine. N-glycoproteins are a particularly attractive class of proteins that constitute potential cancer biomarkers and therapeutic targets for smallmolecules, antibodies, and cellular therapies. Using mass spectr...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 25; pp. 6581 - 6586
Main Authors Rolland, Delphine C.M., Basrur, Venkatesha, Jeon, Yoon-Kyung, McNeil-Schwalm, Carla, Fermin, Damian, Conlon, Kevin P., Zhou, Yeqiao, Ng, Samuel Y., Tsou, Chih-Chiang, Brown, Noah A., Thomas, Dafydd G., Bailey, Nathanael G., Omenn, Gilbert S., Nesvizhskii, Alexey I., Root, David E., Weinstock, David M., Faryabi, Robert B., Lim, Megan S., Elenitoba-Johnson, Kojo S. J.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 20.06.2017
Subjects
Anaplastic large-cell lymphoma
Antibodies
Biological Sciences
Biomarkers
Biomarkers, Tumor - genetics
Biotechnology
Cancer
Cell Line, Tumor
Clustering
Gene expression
Genomes
Genomics
Glycoproteins
Humans
Immunology
Integration
Lymphoma
Lymphoma - genetics
Mass spectrometry
Mass spectroscopy
Molecules
Precision medicine
Protein-tyrosine kinase
Proteins
Proteogenomics - methods
Proteomics
Receptor Protein-Tyrosine Kinases - genetics
Signal Transduction - genetics
Target recognition
Transcription factors
Transcriptome - genetics
Tumor cell lines
CRISPR screen
RNA-seq
proteomics
biomarkers
lymphoma
Online AccessGet full text
ISSN0027-8424
1091-6490
1091-6490
DOI10.1073/pnas.1701263114

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Summary:Identification of biomarkers and therapeutic targets is a critical goal of precision medicine. N-glycoproteins are a particularly attractive class of proteins that constitute potential cancer biomarkers and therapeutic targets for smallmolecules, antibodies, and cellular therapies. Using mass spectrometry (MS), we generated a compendium of 1,091 N-glycoproteins (from 40 human primary lymphomas and cell lines). Hierarchical clustering revealed distinct subtype signatures that included several subtype-specific biomarkers. Orthogonal immunological studies in 671 primary lymphoma tissue biopsies and 32 lymphomaderived cell lines corroborated MS data. In anaplastic lymphoma kinase-positive (ALK⁺) anaplastic large cell lymphoma (ALCL), integration of N-glycoproteomics and transcriptome sequencing revealed an ALK-regulated cytokine/receptor signaling network, including vulnerabilities corroborated by a genome-wide clustered regularly interspaced short palindromic screen. Functional targeting of IL-31 receptor β, an ALCL-enriched and ALK-regulated N-glycoprotein in this network, abrogated ALK⁺ALCL growth in vitro and in vivo. Our results highlight the utility of functional proteogenomic approaches for discovery of cancer biomarkers and therapeutic targets.
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1D.C.M.R., V.B., and Y.-K.J. contributed equally to this work.
Edited by Louis M. Staudt, National Cancer Institute, NIH, Bethesda, MD, and approved May 2, 2017 (received for review January 23, 2017)
Author contributions: D.C.M.R., V.B., C.M.-S., M.S.L., and K.S.J.E.-J. designed research; D.C.M.R., V.B., Y.-K.J., C.M.-S., K.P.C., S.Y.N., N.A.B., D.G.T., N.G.B., D.E.R., and D.M.W. performed research; D.C.M.R., D.F., Y.Z., C.-C.T., A.I.N., and R.B.F. analyzed data; and D.C.M.R., V.B., G.S.O., R.B.F., M.S.L., and K.S.J.E.-J. wrote the paper.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1701263114