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Altered expression of CSF3R splice variants impacts signal response and is associated with SRSF2 mutations. | LitMetric

AI Article Synopsis

  • - Three splice variants of the CSF3R mRNA have been identified: CSF3R-V1 is the standard receptor, CSF3R-V4 is a truncated version found in some acute myeloid leukemia (AML) patients, and CSF3R-V3 was previously detected in placenta but is not well understood.
  • - A new digital PCR method showed that CSF3R-V1 is the most expressed variant in hematopoietic cells, while CSF3R-V3, though less prevalent, expresses a hypoproliferative phenotype that can be improved by coexpression with V1.
  • - Analysis of CD34+ cells revealed a significant increase in the V3/V1 ratio in

Article Abstract

Three annotated CSF3R mRNA splice variants have been described. CSF3R-V1 is the wild-type receptor, while CSF3R-V4 is a truncated form increased in some patients with AML. CSF3R-V3 mRNA was identified in placenta more than 20 years ago, but remains largely uncharacterized due to the lack of a suitable detection assay. Using a novel digital PCR method to quantitate expression of each CSF3R mRNA splice variant in hematopoietic cells, CSF3R-V1 was most highly expressed followed by CSF3R-V3. Functional assays revealed expression of V3 alone conferred a hypoproliferative phenotype associated with defective JAK-STAT activation. However, coexpression of V1 with V3 rescued proliferative responses. Comparative analysis of V3/V1 expression in CD34+ cells from healthy donors and patients with AML revealed a statistically significant increase in the V3/V1 ratio only in the subset of patients with AML harboring SRSF2 mutations. Knockout of SRFS2 in KG-1 and normal CD34+ cells decreased the V3/V1 ratio. Collectively, these data are the first to demonstrate expression of the CSF3R-V3 splice variant in primary human myeloid cells and a role for SRSF2 in modulating CSF3R splicing. Our findings provide confirmatory evidence that CSF3R is a target of SRSF2 mutations, which has implications for novel treatment strategies for SRSF2-mutated myeloid malignancies.

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Source
http://dx.doi.org/10.1038/s41375-019-0567-9DOI Listing

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