25 March 2019

New discoveries have been made about a protein that plays a key role in acute myeloid leukaemia (AML), suggesting it has a ‘contradictory’ role in the disease.

The protein, EZH2, can supress the development of AML, but then helps maintain tumour growth once the leukaemia is established, according to researchers.

Prof Brian Huntly of the Cambridge Institute for Medical Research and his team explain that EZH2 influences the activity of hundreds of genes, by making chemical changes to the histone proteins which package up DNA into chromosomes.

It has previously been found that raised EZH2 activity is linked to the development of many forms of cancer, including breast and prostate cancers. The study, published in the Journal of Experimental Medicine, investigated whether EZH2 also promotes the development of blood cancers, or helps prevent them.

The study looked at mice which lack the Ezh2 gene. These animals developed AML at an increased rate, suggesting that Ezh2 is a tumour suppressor in the initiation phase of leukaemia.

However, further tests which removed or inhibited Ezh2 once the cancer had developed revealed that it slows tumour growth and prolonged survival at this stage. Blocking the EZH2 protein in human AML cell lines and samples donated by patients was also shown to slow cancer cell growth.

This contradictory action can be explained because EZH2 regulates different sets of genes at different disease stages, the researchers say.

Prof Huntly said: “Our findings uncover novel and dramatically opposing functions of EZH2 during acute myeloid leukaemia that appear dependent upon the phase of disease, with EZH2 functioning as a tumour suppressor in acute myeloid leukaemia induction and as a facilitator of disease in established acute myeloid leukaemia.

“To our knowledge, this is the first description of an epigenetic regulator having both tumour-suppressive and oncogenic function in different phases of the same cancer. In addition, our work validates EZH2 as a therapeutic target with the potential to treat several different subtypes of acute myeloid leukaemia.”

Source: Basheer, F., Giotopoulos, G., Meduri, E., Yun, H., Mazan, M., Sasca, D., Gallipoli, P., Marando, L., Gozdecka, M., Asby, R., Sheppard, O., Dudek, M., Bullinger, L., Döhner, H., Dillon, R., Freeman, S., Ottmann, O., Burnett, A., Russell, N., Papaemmanuil, E., Hills, R., Campbell, P., Vassiliou, G.S., Huntly B.J.P. (2019) “Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML”, Journal of Experimental Medicine, available from doi: 10.1084/jem.20181276


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