Pathologic interaction between megakaryocytes and polymorphonuclear leukocytes in myelofibrosis

Idiopathic myelofibrosis (MF) is a myeloproliferative syndrome characterize d by an increase in bone marrow collagen. Megakaryocytes (Mks), which store growth factors in their alpha granules, are known to be involved in the pa thogenesis of MF. Previously, mice given bone marrow grafts infected with a retrovirus carrying murine thrombopoietin (TPO) complementary DNA develope d a disease resembling human idiopathic MF, In this study, we used this mur ine model (TPO mice) to determine whether release of alpha granules is resp onsible for fibroblast activation and development of fibrosis, The intracel lular trafficking of several alpha-granule proteins (von Willebrand factor, fibrinogen, and transforming growth factor beta (TGF beta), which are stor ed in the granule matrix; and alpha(IIb)beta(3) integrin and P-selectin (CD 62p), which are located in the alpha-granule membrane) was studied with imm une electron microscopy in bone marrow Mks from TPO mice. P-selectin immuno labeling increased consistently and was occasionally found lining the demar cation membrane system. Evidence of extensive emperipolesis was also found in TPO mouse Mks, involving almost exclusively neutrophil and eosinophil po lymorphonuclear (PMN) cells with altered morphologic features. In parallel, the host Mks had myeloperoxidase-positive granules scattered in their cyto plasm, associated with marked ultrastructural cytoplasmic alterations and r uptured alpha-granule membranes. Similar observations were made in bone mar row 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 st udy indicates that in idiopathic MF, abnormal P-selectin distribution in Mk s induces selective sequestration of PMN cells. This results in a release o f alpha-granular proteins and growth factors, which in turn induces fibrobl ast activation and fibrosis deposition. (Blood, 2000;96: 1342-1347) (C) 200 0 by The American Society of Hematology.