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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1342-1347
HEMATOPOIESIS
Pathologic interaction between megakaryocytes and
polymorphonuclear leukocytes in myelofibrosis
Alain Schmitt,
Hélène Jouault,
Josette Guichard,
Françoise Wendling,
Arnaud Drouin, and
Elisabeth M. Cramer
From INSERM U.474 and Laboratoire d'Hématologie, Hôpital
Henri Mondor, Créteil, France; and INSERM U.362, Institut Gustave
Roussy, Villejuif, France.
Idiopathic myelofibrosis (MF) is a myeloproliferative syndrome
characterized by an increase in bone marrow collagen. Megakaryocytes (Mks), which store growth factors in their  granules, are known to
be involved in the pathogenesis of MF. Previously, mice given bone
marrow grafts infected with a retrovirus carrying murine thrombopoietin
(TPO) complementary DNA developed a disease resembling human idiopathic
MF. In this study, we used this murine model (TPO mice) to determine
whether release of granules is responsible for fibroblast
activation and development of fibrosis. The intracellular trafficking of several -granule proteins (von Willebrand factor, fibrinogen, and transforming growth factor  (TGF),
which are stored in the granule matrix; and
IIb3 integrin and P-selectin (CD62p),
which are located in the -granule membrane) was studied with immune
electron microscopy in bone marrow Mks from TPO mice. P-selectin
immunolabeling increased consistently and was occasionally found lining
the demarcation membrane system. Evidence of extensive emperipolesis
was also found in TPO mouse Mks, involving almost exclusively
neutrophil and eosinophil polymorphonuclear (PMN) cells with altered
morphologic features. In parallel, the host Mks had
myeloperoxidase-positive granules scattered in their cytoplasm, associated with marked ultrastructural cytoplasmic alterations and
ruptured -granule membranes. Similar observations were made in bone
marrow biopsy specimens from 12 patients with idiopathic MF; indeed,
there was an increased rate of emperipolesis involving mostly PMN
cells, abnormal P-selectin expression, and mutual subcellular PMN and
Mk alterations. This study indicates that in idiopathic MF, abnormal
P-selectin distribution in Mks induces selective sequestration of PMN
cells. This results in a release of -granular proteins and growth
factors, which in turn induces fibroblast activation and
fibrosis deposition.
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