MOLECULAR ADVANCES TOWARD THE UNDERSTANDING OF THE PATHO-BIOLOGY OF IDIOPATHIC MYELOFIBROSIS

Chronic idiopathic myelofibrosis (IM) is a chronic myeloproliferative disorder characterized by splenomegaly, a leukoerythroblastic blood picture, teardrop poikilocytosis, marrow fibrosis, osteosclerosis, marrow neo-vascularization, abnormal stem/progenitor cell trafficking and extramedullary hematopoiesis. The disease may eventually evolve into acute leukemia. This Philadelphia chromosome negative disorder is thought to originate from a somatic mutation at the level of the multipotent hematopoietic stem cell, the most visible consequence of which is a profound hyperplasia associated with increased proliferation but abnormal differentiation of the megakaryocytes (MKs). The pathobiology of the disease, however, involves not only abnormal hematopoietic stem/progenitor cells functions, but also a defective marrow microenvironment. The molecular nature of the genetic defect in IM and how this defect might induce so many pleiotropic consequences remains unknown. Many of the features of the human disease can be reproduced in mice by genetic alterations that induce MK abnormalities similar to those found in patients. Unfortunately, none of the mutations causing the disease in mice has been detected in the human disease. These animal models, however, allow one to dissect the patho-biological pathway that establishes the complex features of IM. Furthermore, these models also shed light on the cross-talk between stem/progenitor cells and microenvironment in normal hematopoiesis.