29 June 2020

US scientists have discovered an important role for a protein in primary myelofibrosis (PMF), which could eventually lead to a new treatment approach to help patients.

Researchers at the Boston University School of Medicine have shown that inhibiting α5β1 integrin decreases the number of megakaryocytes, in both in vivo and in vitro experimental models.

An increase in megakaryocyte numbers is thought to be the cause of problems observed in this disease, the researchers say.

Most drug development for PMF so far has focused on the JAK2V617F mutation, which is the major driver mutation in the condition. However, the team believes this approach has failed to change the course of disease.

In a mouse model, the researchers introduced the mutated JAK2V617F gene to induce symptoms of myeloproliferative neoplasms. The team then used an antibody against α5 (one of the proteins that makes up α5β1 integrin) to block the ability of cells to bind to fibronectin, which is abundant in fibrotic bone marrow.

They found that this led to a decrease in the number of megakaryocytes in bone marrow, compared to a control group of mice without the JAK2V617F mutation. These findings were then replicated in the lab using human cells donated by patients with PMF and healthy controls.

Lead author Dr Shinobu Matsuura, instructor of medicine at Boston University School of Medicine, said: “Our study has taken a totally new approach for treatment of the disease, which, if successful, will present a complementary or even an alternative therapy to existing treatments.”

Publishing their results in the journal Blood, the researchers say they hope to find effective treatments for myelofibrosis, which can occur secondary to many diseases and is a terminal condition with no specific treatment available.

They write: “Myeloproliferative neoplasms are a chronic and debilitating disease. Safe and effective novel treatments of this disease will improve the quality of life of these patients.”

Source: Matsuura S, Thompson CR, Ng SK, Ward CM, Karagianni A, Mazzeo C, Malara A, Balduini A, Ravid K (2020) “Adhesion to fibronectin via α5β1 integrin supports expansion of the megakaryocyte lineage in primary myelofibrosis”, Blood, doi: 10.1182/blood.2019004230


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