Markedly reduced expression of platelet c-mpl receptor in essential thrombocythemia.
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 TPO-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.
Horikawa
Y
Y
Department of Internal Medicine II, Osaka University Medical School, Osaka, Japan.
Matsumura
I
I
Hashimoto
K
K
Shiraga
M
M
Kosugi
S
S
Tadokoro
S
S
Kato
T
T
Miyazaki
H
H
Tomiyama
Y
Y
Kurata
Y
Y
Matsuzawa
Y
Y
Kanakura
Y
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001792:Blood Platelets / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic / Q000096:biosynthesis; D053628:Receptors, Thrombopoietin; D013922:Thrombocytosis / Q000097:blood*; D013926:Thrombopoietin / Q000378:metabolism*
C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin