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Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):6581-6586. doi: 10.1073/pnas.1701263114. Epub 2017 Jun 12.

Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas.

Author information

1
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
2
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
3
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
4
Department of Pediatrics,University of Michigan Medical School, Ann Arbor, MI 48109.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
6
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
7
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109.
8
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109.
9
The Broad Institute of Massachusetts Institute of Technology and Harvard Medical School, Boston, MA 02142.
10
Center for Personalized Diagnostics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.
11
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104; kojo.elenitoba-johnson@uphs.upenn.edu megan.lim@uphs.upenn.edu.

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.

KEYWORDS:

CRISPR screen; RNA-seq; biomarkers; lymphoma; proteomics

PMID:
28607076
PMCID:
PMC5488937
DOI:
10.1073/pnas.1701263114
[Indexed for MEDLINE]
Free PMC Article

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