Blocking cellular 'free-cycling' may slow bone marrow scarring in myelofibrosis

In a new study published in Nature Communications, Boston Children's Hospital researchers identified a new target responsible for scar formation in the bone marrow of patients with a type of blood cancer known as myelofibrosis. Combining traditional myelofibrosis therapy with drugs that block scar formation may be a more effective treatment for patients with the disease.

"The current gold standard treatment for myelofibrosis targets the symptoms but is not curative," says Joseph Italiano Jr., Ph.D., principal investigator in the Vascular Biology Program at Boston Children's. "Based on our findings, we believe that if we can delay scarring, it may give people more time and improve lives."

How scarring drives the disease

Myelofibrosis typically occurs in older adults who often don't receive a diagnosis until the condition has progressed. Accompanying symptoms, such as feeling tired, bruising easily or having pain in the side of the abdomen, can appear innocuous, though they may indicate damage already occurring in the bone marrow, the soft, spongy tissue inside your bones that harbors stem cells. Prognosis is poor, with an average life expectancy of five to seven years.

In the bone marrow, platelet-making cells, known as megakaryocytes, control blood cell production by releasing chemical messengers, known as cytokines, that relay instructions to blood stem cells. In myelofibrosis, the message changes, causing excessive scar tissue formation in the bone marrow. This process reduces stem cells' ability to produce healthy new blood cells as they run out of space.

A recycling pathway gone awry

Through a series of experiments, Italiano and Isabelle Becker, Ph.D., a postdoctoral fellow in his laboratory, determined how megakaryocytes release scar-building chemical messages. Typically, cells redirect unwanted or damaged proteins to internal recycling centers. However, in megakaryocytes, these recycling centers fuse with the cell membrane and dump their contents outside the cell—essentially offering scar-building cytokines to other cells via 'freecycling.'

Drugs that block this freecycling activity, such as the antimalarial drug hydroxychloroquine, prevented scar-building chemical messages from reaching the bone marrow space, and scar tissue stopped forming in mouse models of myelofibrosis. Mutations in the protein JAK2 often occur in people with the disease, and as a result, JAK2 inhibitors are the first-line treatment. When researchers combined the freecycling blocker with a traditional treatment like the JAK2 inhibitor ruxolitinib, mice had less scarring in their bone marrow and fewer blood cell abnormalities.

"The problem with the current JAK2 inhibitors is that they can stop working as the cancer evolves to become resistant," says Becker. "We hope that by attacking the cancer by multiple mechanisms, we will be more likely to outmaneuver it."

The researchers plan to review the freecycling mechanism in other animal models and test other drugs that may prevent bone marrow scarring.

This article was originally published on MedicalXpress Breaking News-and-Events.