Drug target potential for myelofibrosis

A new paper led by Dr Bethan Psaila, from the Weatherall Institute of Molecular Medicine (WIMM) of the Radcliffe Department of Medicine, has revealed a potential new immunotherapy drug target in the treatment of myelofibrosis.

Myelofibrosis is an uncommon type of bone marrow cancer characterised by gene mutations acquired in blood stem cells that lead to over-production of bone marrow cells called megakaryocytes, development of scarring or ‘fibrosis’ that stops the bone marrow being able to produce blood cells in adequate numbers, low blood counts and a large spleen.

At present, bone marrow transplant is the only potentially curative treatment for myelofibrosis, but this procedure carries high risks and only a small proportion of patients are suitable candidates for this. While drug therapies including JAK inhibitors can improve symptoms and quality of life, none are curative and these do not improve the bone marrow fibrosis. Therefore, there is a need to identify new targets for therapeutic development.

In a paper recently published in Molecular Cell, Beth Psaila and her team investigated a specific aspect of myelofibrosis, which is an increased frequency of bone marrow megakaryocyte (MK) cells. MKs are the bone marrow cell responsible for the production of platelets. While they are rare cells in healthy bone marrow, a pathogenomic feature of myelofibrosis is that they are observed in high numbers, and they are recognised as the key cellular drivers of fibrosis.

In order to better understand the cellular and molecular pathways leading to over-production of Mks and their dysfunction, the team used single-cell analyses, studying over 120,000 blood stem/progenitor cells individually.

This led to two key observations: firstly, that the proportion of blood stem cells that were genetically ‘primed’ to give rise to MKs was 11-fold higher in myelofibrosis patients than in healthy donors, and secondly that MK genes were being switched on even in the most primitive stem cells in myelofibrosis, suggesting massive expansion of a ‘direct’ route for MKs to develop from stem cells in myelofibrosis, a phenomenon that was almost undetectable in healthy bone marrow.

They found that the myelofibrosis stem/progenitor cells, but not the wild-type or normal stem cells, expressed a high level of G6B, a immunoglobulin cell-surface receptor protein. They validated G6B as an exciting potential immunotherapy target that might be utilised to specifically ablate both the cancer stem cell clone and the fibrosis-driving MK cells.

Dr Beth Psaila commented:

“The finding that G6B is markedly increased in the cancer stem cells is very important, as it suggests that targeting G6B in combination with a stem cell marker may be a way of selectively targeting the cancer-driving stem cells while sparing healthy stem cells.

“Identifying ways to knock out the disease-initiating cells is crucial to make progress in this disease, as currently there are no curative treatments available to offer the majority of our patients.”

Going forward, Beth and her team will be working on further validating their targeting strategy to see if it might be translated to the clinic.

About Beth

Beth is a CRUK Advanced Clinician Scientist at the MRC Weatherall Institute of Molecular Medicine. The primary focus of her group is on megakaryocyte and platelet biology in cancer, and the application of single-cell approaches to clarify the cellular pathways by which megakaryocytes arise from haematopoietic stem cells.

She trained at Clare College, Cambridge, Imperial College London/The Hammersmith Hospital, Cornell, New York, and the National Institutes of Health, Bethesda USA, Beth is also an Honorary Consultant in Haematology in Oxford and a Senior Fellow in Medicine of New College, Oxford.

This research was conducted in collaboration with Prof Adam Mead and Dr Supat Thongjuea in the WIMM, including using data that was generated by Dr Alba Rodriguez-Meira. The work was partially funded by a Cancer Research UK Advanced Clinician Scientist Fellowship, a CRUK Innovation Award; a Wellcome Career Development Fellowship and a Medical Research Council (MRC) Senior Clinical Fellowship.