5 years ago

Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas [Medical Sciences]

Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas [Medical Sciences]
David M. Weinstock, Gilbert S. Omenn, Kojo S. J. Elenitoba-Johnson, Kevin P. Conlon, Megan S. Lim, David E. Root, Nathanael G. Bailey, Dafydd G. Thomas, Noah A. Brown, Chih-Chiang Tsou, Samuel Y. Ng, Yoon-Kyung Jeon, Venkatesha Basrur, Delphine C. M. Rolland, Damian Fermin, Robert B. Faryabi, Alexey I. Nesvizhskii, Carla McNeil-Schwalm, Yeqiao Zhou

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 small molecules, 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 lymphoma-derived 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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