In a new study published in Nature Communications , Boston Children's Hospital researchers have 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 the scar formation may be a more effective method for treating patients with the disease.
"The current gold standard treatment for myelofibrosis targets the symptoms but is not curative," says Joseph Italiano, Jr, PhD , 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."
Myelofibrosis typically occurs in older adults who often don't receive a diagnosis until the condition has progressed. The accompanying symptoms such as feeling tired, bruising easily, or having pain in the side abdomen can appear innocuous, though they may be an indicator of damage already occurring in the bone marrow, the soft spongy tissue inside your bones responsible for harboring 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 production of blood cells by releasing chemical messengers, known as cytokines, to relay instructions to blood stem cells. In myelofibrosis, the message changes, causing excessive scar tissue formation in the bone marrow. This process reduces the stem cell's ability to produce new healthy blood cells as they run out of space.
Through a series of experiments, Italiano and Isabelle Becker, PhD, a postdoctoral fellow in his laboratory, determined how megakaryocytes release the scar-building chemical messages. Typically, cells redirect their unwanted or damaged proteins to internal recycling centers. However, in the case of megakaryocytes and their scar-building cytokines, these recycling centers fuse with the cell membrane and dump their contents outside of the cell — essentially offering them up to other cells via 'freecycling.'
By using drugs that block this freecycling activity, such as the antimalarial drug hydroxychloroquine, and thus preventing the scar-building chemical messages from reaching the bone marrow space, scar tissue in mouse models of myelofibrosis stopped forming. Mutations in the protein JAK2 often occur in people with the disease, and as a result JAK2 inhibitors are the first line of treatment. When combining 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.
