# Targeting ligand-independent CSF3R dimerization in chronic neutrophilic leukemia

> **NIH NIH F31** · STANFORD UNIVERSITY · 2020 · $37,706

## Abstract

The modification of proteins with carbohydrates, called glycosylation, is commonly dysregulated in cancer. One
example is chronic neutrophilic leukemia (CNL), a rare disease characterized by the uncontrolled growth of
neutrophils. Over 80% of published CNL cases result from a mutation in the colony-stimulating factor 3 receptor
(CSF3R). This mutation results in decreased O-linked glycosylation as well as increased ligand-independent
dimerization. However, the relationship between these two findings is not known and there are no therapies that
target the mutated epitope. The central hypothesis of this project is the loss of glycosylation decreases steric
hindrance for CSF3R dimerization and reveals a cancer-specific epitope for targeted therapy. In Aim 1, mass
spectrometry will identify the glycans that are present on the wild-type protein but missing in the mutated variant.
Additionally, crystal structures of mutant CSF3R will reveal how the loss of glycosylation remodels the receptor
interface and promotes ligand-independent dimerization. In Aim 2, screens of yeast-displayed proteins will
identify candidates which bind to mutated, but not wild-type CSF3R. Biologics specific to the mutated protein will
be validated for labeling cells and blocking dimerization in vitro, and selectively eliminating cancer cells in a
mouse model of CNL. Combined, this work will demonstrate how understanding the structural effects of
glycosylation facilitates drug discovery. This work is co-sponsored at Stanford University by Drs. Jennifer
Cochran and Carolyn Bertozzi, leaders in protein engineering and glycobiology, respectively. This project is also
supported through a collaboration with Dr. Julia Maxson, who first discovered the CSF3R mutation. This doctoral
work will provide essential training for a research career, bridging the gap between molecular mechanisms of
cancer and drug development.

## Key facts

- **NIH application ID:** 10011556
- **Project number:** 5F31CA243267-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Michael Hollander
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,706
- **Award type:** 5
- **Project period:** 2019-09-30 → 2021-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011556

## Citation

> US National Institutes of Health, RePORTER application 10011556, Targeting ligand-independent CSF3R dimerization in chronic neutrophilic leukemia (5F31CA243267-02). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10011556. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*