Researchers find mutation for rare genetic blood disorder

UW-Madison researchers have honed in on a specific mutation which causes myelofibrosis, a rare genetic blood disorder.

Dr. Inga Hofmann is an assistant professor of pediatrics and medical director for the UW Program for Advanced Cell Therapy. She began her journey to understand myelofibrosis in 2010, after several cases were referred to her for a second opinion.

The results of that 8-year exploration were published recently in the scientific journal Blood.

Myelofibrosis is a disorder of the bone marrow that disrupts production of red blood cells. According to UW-Madison’s School of Medicine and Public Health, childhood cases of the disorder are usually caused by a blood cancer called megakaryoblastic leukemia.

However, when the disorder comes from a genetic origin, and that cancer isn’t present, the cause was previously unknown. Hofmann and her team determined that mutations in a protein controlling blood platelet production seem to be the source of a certain type of myelofibrosis.

“This is the first cause ever identified,” she said.

The disease can result in bone marrow scarring, weakness, anemia and an enlarged spleen. Only 50 cases of the disease have ever been recorded, and the only current treatment is a stem cell transplant.

Researchers found that specific protein — known as G6b-B — can be altered to boost production of blood cells, which could be exploited to find new treatment options.

Hofman met the first referred case when she was working as a pediatric hematology specialist at Boston Children’s Hospital. Though it was nearly impossible to find the cause based on one case, genetic analysis of the next two she came across helped pinpoint the mutated protein in question.

Further evidence came in 2017, when research collaborator Yotis Senis came forward with a fourth case of the specific genetic mutation. Senis, a professor at the University of Birmingham in England, is a respected blood platelet researcher with expert knowledge of the target protein identified by Hofmann.

After that point, Hofmann and Senis combined their efforts to understand the role of the mutated protein and find new ways to treat affected individuals.

“If we could manipulate the pathway involving the G6b-B protein in myelofibrosis patients, we might be able to restore normal platelet producing cells in the bone marrow cells and stimulate the production of normal blood cells,” Hofmann said. “This is a real paradigm-shifting idea.”