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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2555-2561
Posttranslational Processing of the Thrombopoietin Receptor Is
Impaired in Polycythemia Vera
Alison R. Moliterno and
Jerry L. Spivak
From the Division of Hematology, Department of Medicine, Johns
Hopkins University School of Medicine, Baltimore, MD.
Recently, we demonstrated a marked reduction in the expression of
the thrombopoietin receptor, Mpl, in polycythemia vera (PV) platelets
and megakaryocytes using an antiserum against the Mpl extracellular
domain. To further examine this abnormality, we raised an antibody to
the Mpl C-terminus. Immunologic analysis of PV platelets with this
antiserum confirmed the reduction in Mpl expression. However, the
C-terminal antiserum detected 2 forms of Mpl in PV platelets in
contrast to normal platelets, in which a single form of Mpl was
detected by both the extracellular domain and C-terminal antisera.
Two-dimensional gel electrophoresis studies with isoelectric focusing
in the first dimension identified normal platelet Mpl as an 85 to 92 kD
protein with an isoelectric point (pI) of 5.5. PV platelets contained
an additional 80 to 82 kD Mpl Mpl isoform with a pI of
6.5. Analysis of Mpl expressed by the human megakaryocytic cell line,
Dami, showed 2 isoforms similar to those found in PV platelets
suggesting a precursor-product relationship. Digestion of Dami cell and
normal platelet lysates with neuraminidase converted the more acidic
Mpl isoform to the more basic one, indicating that the 2 isoforms
differed with respect to posttranslational glycosylation. Futhermore,
in contrast to normal platelet Mpl, PV platelet Mpl was susceptible to
endoglycosidase H digestion, indicating defective Mpl processing by PV
megakaryocytes. The glycosylation defect was specific for Mpl, as 2 other platelet membrane glycoproteins, glycoprotein IIb and multimerin,
were processed normally. Importantly, the extent of the PV platelet Mpl
glycosylation defect correlated with disease duration and extramedullary hematopoiesis.
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