10 May 2019

A new therapeutic target has been identified which could be the key to halting progression of acute myeloid leukaemia (AML) in almost one-fifth of patients, researchers have reported.

Researchers from the Cincinnati Children’s Hospital Medical Center, USA, studied a complex molecular machine known as the ‘spliceosome’, which is responsible for cutting and gluing together sections of RNA in the nucleus of the cell. They found that mutations in one of the key spliceosome components leads to the production of a hyperactive form of a protein called IRAK4, which causes cells to become cancerous.

The team blocked the hyperactive form of IRAK4 in laboratory tests with AML cell lines and primary AML cells from patients transplanted into immunosuppressed mice, and found there was a significant reduction of leukaemia cells.

The team, which was led by Dr Daniel Starczynowski and included scientists from eight institutions in the U.S. and the University of Oxford, are now testing existing drugs that can target hyperactive IRAK4 in leukaemia cells.

They are also developing a new drug that more effectively inhibits hyperactive IRAK4 to treat AML and its precursor disease, myelodysplastic syndromes.

Dr Starczynowski, whose study is published in Nature Cell Biology, said he wanted the inhibitor to be ready for clinical tests within a few years, because the need for new treatments is urgent.

“There is very little we can do for these patients,” he said. “Even new drugs now getting fast-tracked through the development process may only produce another six months of survival. The curative option is a bone marrow transplant, but most of these patients don't qualify."

The researchers think that the findings could potentially benefit a subset of about 20% of AML-MDS patients. The study also paves the way for finding other subsets of AML that depend on a hyperactive IRAK4 as a result of mutations in the spliceosome machinery.

Source: Smith, M.A., Choudhary, G.S., Pellagatti, A., Choi, K., Bolanos, L.C., Bhagat, T.D., Gordon-Mitchell, S., Von Ahrens, D., Pradhan, K., Steeples, V., Kim, S., Steidl, U., Walter, M., Fraser, I.D.C., Kulkarni, A., Salomonis, N., Komurov, K., Boultwood, J., Verma, A., Starczynowski, D.T. (2019) “U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies”, Nature Cell Biology, available from doi: 10.1038/s41556-019-0314-5


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