Alternatively spliced CSF3R isoforms in SRSF2 P95H mutated myeloid neoplasms

Area of Science:

• Molecular Biology
• Hematology
• Cancer Research

Background:

• Alternatively spliced colony stimulating factor 3 receptor (CSF3R) isoforms, Class III and IV, are present in myelodysplastic syndromes (MDS).
• The specific roles of these CSF3R isoforms in MDS pathogenesis are not well understood.

Purpose of the Study:

• To investigate the role of the splicing factor SRSF2 in regulating CSF3R isoforms (Class III and IV).
• To determine the impact of SRSF2 mutations on granulopoiesis and CSF3R splicing in myeloid neoplasms.

Main Methods:

• Utilized in vitro splicing assays with CSF3R minigene and SRSF2 mutants in K562 cells.
• Analyzed CSF3R isoform expression in CD34+ cells from patients with myeloid neoplasms and SRSF2 mutations.
• Performed add-back experiments of CSF3R isoforms in Csf3r-null mouse progenitor cells.

Main Results:

• Mutated SRSF2 (P95) was found to affect Class III and IV CSF3R isoform expression, leading to perturbed granulopoiesis.
• Add-back of Class IV isoform in progenitor cells resulted in increased granulocyte progenitors with impaired neutrophil differentiation.
• Add-back of Class III isoform led to fewer, dysmorphic neutrophils.
• Elevated CSF3R isoforms were observed in patients with myeloid neoplasms harboring SRSF2 mutations.
• SRS F2 P95H mutation promoted Class IV splicing by binding to exonic splicing enhancer (ESE) sequences in CSF3R exon 17, impairing neutrophil differentiation.

Conclusions:

• Mutated SRSF2 contributes to dysgranulopoiesis by promoting Class IV CSF3R splicing.
• The study elucidates a mechanism by which SRSF2 mutations drive myeloid neoplasm pathogenesis through altered CSF3R splicing.