A signaling pathway has been identified that can be targeted in a novel treatment for leukemia. Leukemia is caused by leukemic stem cells which give rise to abnormal blood cells that do not function correctly. One of the problems with treating leukemia, as opposed to other cancers, is the leukemic stem cells are often resistant to cancer therapies. If the leukemic stem cells are not eradicated, relapses will occur.
Targeting leukemic stem cells is not straightforward, as leukemic stem cells closely resemble stem cells that form normal, healthy blood cells. What is needed is a way to differentiate between the two to allow only the leukemic stem cells to be killed. While there have been considerable advances in the treatment of solid tumors, the new cancer drugs are not effective at treating leukemia.
A study conducted at the Department of Medical Oncology at Inselspital, Bern University Hospital, has identified a signaling pathway that can be targeted to selectively kill leukemic stem cells. Prof. Adrian Ochsenbein and his team identified what they call the LIGHT/LTbR pathway, which is relied upon by leukemic stem cells but not hematopoietic stem cells.
When normal, healthy blood cells are formed, the LIGHT/LTbR pathway is not utilized. The pathway is only utilized to maintain stem cell function during period of increased demand, such as infections, inflammation or in response to chemotherapy. The pathway is activated by immune effector cytokines such as interferon-α, interferon-γ, and tumor necrosis factor-α (TNF-α).
The LIGHT/LTbR pathway is however relied on by leukemic stem cells and results in increased symmetric cell division, which leads to the proliferation of leukemic stem cells. Leukemic stem cells also have more LIGHT binding sites than normal stem cells.
The researchers conducted experiments on animal models of leukemia and blocked the LIGHT/LTbR pathway using monoclonal antibodies. Leukemic mice that had the pathway blocked survived for longer than those that did not.
The researchers believe blocking the LIGHT/LTbR pathway could serve as an effective treatment for myeloid leukemia.
You can read more about the study in the paper – LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells – which was recently published in Nature Communications. DOI: 10.1038/s41467-021-21317-x