Accumulation of an intron-retained mRNA for granulocyte macrophage-colony stimulating factor receptor common β chain in neutrophils of myelodysplastic syndromes

We recently identified a reduction in the neutrophil surface expression of common β chain (βc) of the receptor for granulocyte macrophage-colony stimulating factor (GM-CSF) in the patients with myelodysplastic syndromes (MDS). To determine the etiology of the impaired βc expression, βc mRNA from neutrophilic granulocytes of MDS patients and healthy controls was analyzed by a combination of direct reverse transcriptiase-polymerase chain reaction-based single-strand conformational polymorphism and sequencing. Nine different βc transcripts were detected, but none was specific for MDS. However, one of the transcripts (βc79) containing a 79-base intron insertion between exons V and VI was significantly increased in MDS. This 27-kd isoform consisted of the βc N-terminal 182 amino acids followed by a new 84-amino-acid sequence. βc79 was overexpressed in all MDS subtypes. No genomic mutations were detected within the intron or at the intron/exon boundaries. The isoform is predominantly located in the cytoplasm by Western blot analysis and was unable to generate high-affinity binding sites or transduce a signal for proliferation when coexpressed with the receptor for human GM-CSF α chain. Our study suggests that the accumulation of the abnormal βc transcripts with intron V retention results in the reduction in cell-surface expression of βc observed in MDS.