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Updated: Mar 9, 2026
10:21
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
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Enhanced MAPK signaling is essential for CSF3R-induced leukemia
S Rohrabaugh1, M Kesarwani1, Z Kincaid1
1Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Leukemia
|December 30, 2016
Summary
CSF3R mutations drive chronic neutrophilic leukemia (CNL). Proximal and compound CSF3R mutations induce leukemia by enhancing MAPK signaling, which trametinib can suppress, suggesting MEK1/2 inhibition for CNL treatment.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Mutations in CSF3R (colony-stimulating factor 3 receptor) are implicated in chronic neutrophilic leukemia (CNL).
- Both membrane-proximal and truncation mutations have been associated with CNL onset.
Purpose of the Study:
- To investigate the distinct leukemogenic potential of different CSF3R mutations.
- To elucidate the molecular mechanisms underlying CSF3R-driven leukemogenesis.
- To evaluate the therapeutic efficacy of MEK1/2 inhibition in CNL.
Main Methods:
- Comparative whole-genome expression profiling.
- Biochemical experiments to assess signaling pathways.
- In vivo studies using mouse models of CNL.
- Pharmacological inhibition of MEK1/2 with trametinib.
Main Results:
- Truncation mutations alone were not leukemogenic.
- Proximal and compound CSF3R mutations induced leukemia with distinct latencies (90 and 23 days, respectively).
- Upregulation of Ksr1 and enhanced MAPK signaling were crucial for leukemogenesis.
- Trametinib effectively suppressed leukemia in both proximal and ruxolitinib-resistant compound mutant models.
Conclusions:
- CSF3R proximal and compound mutations drive CNL through a MAPK-dependent pathway.
- MEK1/2 inhibition represents a promising therapeutic strategy for CNL.
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