Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas

Author:

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.

Abstract

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.

Funder

HHS | National Institutes of Health

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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