CSF3R Splicing Regulates Granulopoiesis Via Splice Variant Specific Responses to G-CSF

The granulocyte colony stimulating factor receptor (CSF3R) is a critical regulator of neutrophil production with multiple alternatively spliced variants. The truncated CSF3R-V4 splice variant confers enhanced growth signals, and changes in its expression levels relative to the canonical V1 (wild type) isoform have been implicated in chemotherapy resistance and relapse of AML. We previously demonstrated that the CSF3R-V3 isoform, a variant of V1 with an insertion in the cytoplasmic domain, produces hypoproliferative signals in lymphoid cells in response to G-CSF. We also reported that expression of all three splice variants is significantly altered in AML, suggesting that aberrant CSF3R splicing is involved in the pathogenesis of some myeloid malignancies. The functional signaling capabilities of the different CSF3R isoforms in regulating granulopoiesis remain largely unknown. Herein, we describe a novel myeloid model system and show that the V3 and V4 isoforms generate opposing proliferative signals without effects on myeloid cell differentiation.