Unpaired extracellular cysteine mutations of CSF3R mediate gain or loss of function

Haijiao Zhang, Sophie Means, Anna Reister Schultz, Kevin Watanabe-Smith, Bruno C. Medeiros, Daniel Bottomly, Beth Wilmot, Shannon McWeeney, Tim Kükenshöner, Oliver Hantschel, Jeffrey Tyner

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g., T618I), functionally defective mutations in the extracellular domain of the G-CSF receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here, we describe the first activating mutation in the fibronectin-like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain- and loss-of-function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.

Original languageEnglish (US)
Pages (from-to)4258-4267
Number of pages10
JournalCancer Research
Volume77
Issue number16
DOIs
StatePublished - Aug 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, H., Means, S., Schultz, A. R., Watanabe-Smith, K., Medeiros, B. C., Bottomly, D., Wilmot, B., McWeeney, S., Kükenshöner, T., Hantschel, O., & Tyner, J. (2017). Unpaired extracellular cysteine mutations of CSF3R mediate gain or loss of function. Cancer Research, 77(16), 4258-4267. https://doi.org/10.1158/0008-5472.CAN-17-1052