New insights into the pathogenesis and drug treatment of myelofibrosis

Purpose of review: Myelofibrosis with myeloid metaplasia was first described in 1879, classified as a myeloproliferative disorder in 1951, and characterized as a clonal stem cell disorder in 1978. Despite the passing of time, the molecular basis of the disease has remained elusive although substantial progress has been made regarding the pathogenesis of the associated bone marrow stromal reaction. Advances have also been meager in terms of treatment for disease complications, including anemia, splenomegaly, and leukemic transformation. Recent findings: At the molecular level, a JAK2 tyrosine kinase mutation (JAK2^V617F) has recently been described in a spectrum of myeloproliferative disorders including myelofibrosis with myeloid metaplasia with the reported mutational frequency ranging from 35% to 57% with 9-29% homozygosity. To date, the presence of JAK2^V617F in myelofibrosis with myeloid metaplasia has not been shown to have prognostic relevance. Other recent observations of potential pathogenetic relevance in this disease include the description of a highly specific chromosomal translocation {der(6)t(1;6)(q23;p21)}, the demonstration of an epigenetic downregulation of the retinoic acid receptor-β2 expression in CD34⁺ cells, and the direct implication of transforming growth factor-β1 in thrombopoietin-driven experimental myelofibrosis in mice. From a therapeutic standpoint, benefit to a subset of patients has been demonstrated for both allogeneic stem cell transplantation and novel drugs, including thalidomide and lenalidomide. Summary: Recent advances in the pathogenesis of myelofibrosis with myeloid metaplasia are expected to facilitate the development of molecularly targeted therapy. In the mean time, current management strategies include observation, participation in experimental drug therapy, and allogeneic stem cell transplantation for low-risk, intermediate-risk, and high-risk disease, respectively.