The primary disease process in
myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary
collagen fibrosis,
osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2
tyrosine kinase (V617F) and bcr/abl-negative
myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of
thrombopoietin (TPOhigh mice) or megakaryocyte lineage restricted underexpression of the
transcription factor GATA-1 (GATA-1low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived
transforming growth factor beta1 in inducing
bone marrow fibrosis and stromal cell-derived
osteoprotegerin in promoting
osteosclerosis. However, experimental
myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other
cytokines that are implicated in mediating
myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and
vascular endothelial growth factors. It is currently assumed that such
cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived
elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.