Researchers have identified a cellular pathway that appears to drive the bone marrow scarring characteristic of myelofibrosis, raising the possibility that combining standard treatments with anti-scarring therapies could improve disease control.
Myelofibrosis is a blood cancer in which abnormal bone marrow activity progressively replaces healthy blood-forming tissue with scar tissue. As the marrow becomes increasingly fibrotic, blood stem cells have less space to produce healthy blood cells, contributing to symptoms such as fatigue, bruising and abdominal pain. Current treatments, including JAK2 inhibitors, can control symptoms and disease activity but are not generally curative.
The researchers focused on megakaryocytes, the bone marrow cells responsible for producing platelets. In myelofibrosis, these cells release excessive amounts of cytokines and other signalling molecules that stimulate surrounding cells to produce scar tissue.
The team discovered that megakaryocytes have an unusual way of releasing these scar-promoting signals.
Normally, cells send unwanted or damaged proteins to intracellular compartments where they are broken down and recycled. In megakaryocytes, these compartments can instead fuse with the cell membrane and release their contents outside the cell. This effectively allows scar-promoting cytokines to be “freecycled” into the surrounding bone marrow.
Blocking this process prevented the cytokines from being released and substantially reduced bone marrow fibrosis in mouse models of myelofibrosis.
The researchers found that drugs capable of interfering with this cellular release pathway, including hydroxychloroquine, could suppress scar formation. They then combined this approach with ruxolitinib, a commonly used JAK2 inhibitor. In mouse models, the combination produced greater effects than JAK2 inhibition alone, with less bone marrow scarring and fewer abnormalities in blood cell production.
This could be particularly relevant because myelofibrosis can evolve and become resistant to JAK2-targeted treatment. Blocking fibrosis through a separate mechanism could potentially make it more difficult for the disease to continue progressing even when cancer cells adapt to JAK2 inhibition.
Rather than targeting the cancer cells alone, this approach targets the bone marrow environment that allows disease-associated fibrosis to develop. If confirmed in further studies, combining conventional JAK2 inhibitors with therapies that prevent the release of scar-promoting signals could represent a new strategy for slowing disease progression and extending the period of effective treatment.
Journal article: Becker, I.C., et al. 2026. Inhibition of RhoA-mediated secretory autophagy in megakaryocytes mitigates myelofibrosis in mice. Nature Communicatons.
Summary by Stefan Botha
