Treatment of myelofibrosis (MF), a BCR-ABL-negative myeloproliferative neoplasm, 
is challenging. The only current potentially curative option, allogeneic 
hematopoietic stem cell transplant, is recommended for few patients. The 
remaining patients are treated with palliative therapies to manage MF-related 
anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 
(JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted 
the discovery and clinical development of inhibitors that target JAK2. Although 
treatment with JAK2 inhibitors has been shown to improve symptom response and 
quality of life in patients with MF, these drugs do not alter the underlying 
disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling 
pathway has been shown to play a role in normal hematopoiesis and in the 
tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh 
pathway have been shown to inhibit growth and self-renewal capacity in 
preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh 
and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow 
fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical 
data also suggest that inhibition of the Hh pathway, alone or in combination 
with JAK2 inhibition, may enable disease modification in patients with MF. 
Future studies, including one combining the Hh pathway inhibitor sonidegib and 
the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform 
whether this combination approach can lead to true disease modification.