Myelofibrosis is a clonal disorder characterized by proliferation of dysplastic megakaryocytes with or without bone marrow fibrosis, a diagnosis, associated with progressive mobilization of hematopoietic CD34+ progenitor cells and extramedullary hematopoiesis. It is a rare disease, with an incidence ranging from 0.4 to 1.4 new cases per 100,000 people. Within all these therapies, stem cell transplantation remains the only potentially curative approach.
JAK2 is a cytosolic protein of 130 kDa in mass, member of the family of cytoplasmic tyrosine kinases including JAK1, JAK3 and TYK2. A single valine to phenylalanine mutation at position 617, located in the pseudo-kinase domain, results in increased JAK2 autophosphorylation with subsequent activation of downstream signaling networks. Other treatments have been reported, Androgens, or attenuated androgens such as danazol, improve anemia in 30–40% of cases. The results with IFN-α have been disappointing, and the use of pegylated IFN (Peg-IFN) was studied in two different trials with quite different results.
Ruxolitinib is a JAK1 and JAK2 inhibitor showing 100-fold selectivity over JAK3 and fivefold over TYK2. It inhibits dysregulated JAK signaling associated with myelofibrosis. JAK1 and JAK2 recruit signal transducers and activators of transcription (STATs) to cytokine receptors leading to modulation of gene expression.
Considered the critical role that constitutive JAK2 tyrosine kinase activity plays in the pathophysiology of myelofibrosis, the molecule represents an attractive therapeutic target and has prompted the search and clinical development of JAK2 small molecule inhibitors.