Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia

Yoko Horikawa, Itaru Matsumura, Koji Hashimoto, Masamichi Shiraga, Satoru Kosugi, Seiji Tadokoro, Takashi Kato, Hiroshi Miyazaki, Yoshiaki Tomiyama, Yoshiyuki Kurata, Yuji Matsuzawa, Yuzuru Kanakura

Research output: Contribution to journalArticlepeer-review

159 Citations (Scopus)

Abstract

Thrombopoietin (TPO) is implicated as a primary regulator of megakaryopoiesis and thrombopoiesis through binding to the cytokine receptor c-Mpl (the product of the c-mpl proto-oncogene). In an effort to determine the pathophysiological role of TPO-c-Mpl system in essential thrombocythemia (ET), we have examined the levels of serum TPO and the expression and function of platelet c-Mpl in 17 patients with ET. In spite of extreme thrombocytosis, serum TPO levels were slightly elevated or within normal range in most, if not all, patients with ET (mean ± SD, 1.31 ± 1.64 fmol mL), as compared with normal subjects (0.76 ± 0.21 fmol/mL). Flow cytometric and Western blot analyses revealed that the expression of platelet c-Mpl was strikingly reduced in all patients with ET. Furthermore, the expression of platelet c-mpl mRNA was found to be significantly decreased in the ET patients tested. In contrast, almost identical levels of GPIIb/IIIa protein and mRNA were expressed in platelets from ET patients and normal controls. In addition to expression level, activation state of platelet c-Mpl was investigated in ET patients. Immunoblotting with anti-phosphotyrosine antibody showed that no aberrant protein-tyrosine phosphorylation was observed in platelets of ET patients before treatment with TPO, and the levels of TP-induced protein-tyrosine phosphorylation, including c-Mpl- tyrosyl phosphorylation, roughly paralleled those of c-Mpl expression, suggesting that c-Mpl-mediated signaling pathway was not constitutively activated in platelets of ET patients. These results suggested that the TPO- c-Mpl system may not be directly linked to pathogenesis of ET, and that gene(s) mutated in ET may be important in regulating the levels of c-mpl gene expression in addition to the growth and differentiation of multipotential hematopoietic stem cells.

Original languageEnglish
Pages (from-to)4031-4038
Number of pages8
JournalBlood
Volume90
Issue number10
DOIs
Publication statusPublished - 1997 Nov 15
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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