29 May 2018

A signalling protein could hold the key to the development of acute myeloid leukaemia (AML), according to a US-based study.

A study by scientists at the Albert Einstein College of Medicine in New York, NY, USA, believe interleukin-1 receptor accessory protein (IL1RAP), which is often highly expressed on the surface of leukemic stem cells but generally absent from normal blood stem cells, plays a greater role in the disease than previously thought.

It is hoped that the finding, which is published in the latest edition of Experimental Medicine, could lead to a successful strategy for treating AML and other blood cancers.

Dr Ulrich Steidl and colleagues found that inhibiting or deleting IL1RAP induces the death of AML cells, including leukaemic stem cells, which had been isolated from patients.

The effects were seen in the absence of immune effector cells, which suggests that AML cells depend on IL1RAP. In contrast, antibodies targeting IL1RAP had no effect on the growth and survival of normal blood cells.

IL1RAP works in conjunction with the interleukin-1 receptor to promote an inflammatory signalling pathway that could play a key role in the development of AML.

Dr Steidl and colleagues found that IL1RAP also enhances the activity of two other membrane receptor proteins, FLT3 and c-KIT, which stimulate the proliferation of leukaemic stem cells when activated by their binding partners.

"Our findings show that IL1RAP can amplify multiple key pathways in AML, demonstrating a much broader role for this protein in disease pathogenesis than previously appreciated," said Dr Steidl.

It also suggests that directly targeting IL1RAP with antibodies or specific drug molecules could be even more effective at killing AML cells and that IL1RAP-directed immunotherapies could be even more promising than currently assumed.

"Importantly, as IL1RAP is also overexpressed in the stem cells of chronic myeloid leukaemia and high-risk myelodysplastic syndromes, there is significant therapeutic potential in further developing IL1RAP-directed targeting strategies," added Dr Steidl.

Source: Mitchell, K., Barreyro, L., Todorova, T.I., Taylor, S.J., Antony-Debré, I., Narayanagari, S.R., Carvajal, L.A., Leite, J., Piperdi, Z., Pendurti, G. and Mantzaris, I., 2018. IL1RAP potentiates multiple oncogenic signaling pathways in AML. Journal of Experimental Medicine, pp.jem-20180147.

Link: http://jem.rupress.org/cgi/doi/10.1084/jem.20180147


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