Novel variant isoform of G-CSF receptor involved in induction of proliferation of FDCP-2 cells: Relevance to the pathogenesis of myelodysplastic syndrome

Norihiro Awaya, Hideo Uchida, Yoshitaka Miyakawa, Kentaro Kinjo, Hiromichi Matsushita, Hideaki Nakajima, Yasuo Ikeda, Masahiro Kizaki

研究成果: Article査読

14 被引用数 (Scopus)

抄録

Recent studies have shown that point mutations in granulocyte colony-stimulating factor receptor (G-CSFR) are involved in the pathogenesis of severe congenital neutropenia (SCN) and in the transformation of SCN to acute myelogenous leukemia (AML). It is reasonably speculated that the abnormalities in the signal transduction pathways for G-CSF could be partly responsible for the pathogenesis and the development to AML in patients with myelodysplastic syndromes (MDS). Therefore, we investigated the structural and functional abnormalities of the G-CSFR in 14 patients with MDS and 10 normal subjects. In in vitro colony forming assay, MDS samples showed reduced response to growth factors. However, G-CSF, but not GM-CSF and IL-3, enhanced clonal growth in three cases of high risk patients with MDS (RAEB, RAEB-t, and MDS having progressed to acute myeloid leukemia (AML)) and one low risk patient (RA). Eight out of 14 patients including above 4 patients demonstrated a common deletion of the G-CSFR cDNA; a deletion of three nucleotides (2128-2130) in the juxtamembrane domain of the G-CSFR, which resulted in a conversion of Asn630 Arg631 to Lys630. To assess the functional activities of this deletion in the G-CSFR isoform, a mutant with the same three-nucleotide deletion was constructed by site-directed mutagenesis. FDCP-2 cells expressing the G-CSFR isoform responded to G-CSF, and exhibited proliferative responses than did those cells having wild-type G-CSFR. Moreover, these isoforms showed prolonged activation of STAT3 in response to G-CSF than did the wild-type. These results suggest that the deletion in the juxtamembrane domain of the G-CSFR gives a growth advantage to abnormal MDS clones and may contribute to the pathogenesis of MDS.

本文言語English
ページ(範囲)327-335
ページ数9
ジャーナルJournal of Cellular Physiology
191
3
DOI
出版ステータスPublished - 2002
外部発表はい

ASJC Scopus subject areas

  • 生理学
  • 臨床生化学
  • 細胞生物学

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