Targeting cytokine secretion to ameliorate fibrosis in myeloproliferative neoplasms
Background
Myelofibrosis is a bone marrow cancer characterized by disruptions in blood cell production. This leads to several symptoms such as anemia and an increased risk of infection and bleeding. Primary and secondary myelofibrosis, a subset of myeloproliferative neoplasms caused by mutations in the thrombopoietin receptor (MPL) or its downstream effector, Janus kinase 2 (JAK2), are characterized by the accumulation of megakaryocytes (MKs) in the bone marrow. These aberrantly matured MKs release pro-fibrotic cytokines, such as transforming growth factor β1 (TGF-β1) and interleukin-1β (IL-1β), into the bone marrow, leading to fibrotic alterations that ultimately represent the major cause of mortality in patients with myelofibrosis. Despite the low quality of life of patients affected by this condition, stem cell transplant, which is a high-risk, prohibitively costly procedure, is one of the only options. Other treatments include JAK’s inhibitors which may relieve some of the symptoms but not reverse the condition.
Technology Overview
A research team at Boston Children’s Hospital investigated the localization of TGF-β1 in megakaryocytes (MKs) and found a distinct distribution pattern, suggesting a unique release mechanism. Further analysis revealed that two key pathways, autophagy and RhoA signaling, are hyperactivated, contributing to the development of myelofibrosis. The findings were confirmed in mouse models, establishing the first direct link between autophagy, RhoA signaling, and myelofibrosis. The discovery opens new therapeutic opportunities for patients with myelofibrosis, with the potential for accelerated clinical trials due to the availability of FDA-approved inhibitors for autophagy and RhoA.
Applications
- Effective for patient population who don’t see effects of current standard of care
- Increased efficacy when combined with the current standard of care
Advantages
- Approved FDA inhibitors available
- Likely to obtain an FDA fast-track trial for off-label treatments of Myelofibrosis
- Low production cost
