A novel germline variant in CSF3R reduces N-glycosylation and exerts potent oncogenic effects in leukemia

David R. Spiciarich, Stephen T. Oh, Amy Foley, Seamus B. Hughes, Michael J. Mauro, Omar Abdel-Wahab, Richard Press, Rosa Viner, Sarah L. Thompson, Qiushi Chen, Parastoo Azadi, Carolyn R. Bertozzi, Julia Maxson

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation. Significance: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia

Mutations in the colony-stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as acute myeloid leukemia. Here, we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK–STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked

Original languageEnglish (US)
Pages (from-to)6762-6770
Number of pages9
JournalCancer Research
Volume78
Issue number24
DOIs
StatePublished - Dec 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Spiciarich, D. R., Oh, S. T., Foley, A., Hughes, S. B., Mauro, M. J., Abdel-Wahab, O., Press, R., Viner, R., Thompson, S. L., Chen, Q., Azadi, P., Bertozzi, C. R., & Maxson, J. (2018). A novel germline variant in CSF3R reduces N-glycosylation and exerts potent oncogenic effects in leukemia. Cancer Research, 78(24), 6762-6770. https://doi.org/10.1158/0008-5472.CAN-18-1638