New insights into the pathogenesis and drug treatment of myelofibrosis.
OBJECTIVE
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.


RESULTS
At the molecular level, a JAK2 tyrosine kinase mutation (JAK2) 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 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-beta2 expression in CD34 cells, and the direct implication of transforming growth factor-beta1 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.


CONCLUSIONS
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.
Tefferi
Ayalew
A
Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. tefferi.ayalew@mayo.edu
D000740:Anemia / Q000188:drug therapy; D000818:Animals; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D051379:Mice; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000235:genetics; D013163:Splenomegaly / Q000188:drug therapy; D014178:Translocation, Genetic / Q000235:genetics
C507924:JAK2 protein, human; D053614:Janus Kinase 2