New ‘poison’ discovery could pave way for leukaemia therapy

WASHINGTON - Research led by Weill Cornell Medical College revealed that newly identified mutant enzymes in AML create a chemical poison to cause leukaemia.

The findings should prove useful in treating patients by providing a molecular target against which to develop new drugs against one subset of AML as well as other cancers.

People with AML have abnormal cells inside their bone marrow that quickly multiply, replacing healthy blood cells in the bone marrow and leading to infections, bleeding and severe anaemia.

Using computational tools to sift through millions of data points, the team discovered a unique chemical signature in the genomes of patients with mutations in either of two enzymes called IDH1 and IDH2, which occur frequently in AML.

Dr. Ari Melnick, Dr. Craig B. Thompson, Dr. Ross L. Levine and their team members discovered that this chemical signature: a massive accumulation of DNA methylation that causes genes to function abnormally, leading to AML.

They went on to show that IDH1 and IDH2 mutations generate a “poison” that blocks the ability of a protective factor called TET2 to remove the methylation from the genome.

They also showed that many AML patients have mutations that inactivate TET2, and this causes the same abnormal DNA methylation effect as IDH1 and IDH2 mutations.

“One of the great surprises of this study was that IDH1 and IDH2, which are normally involved in energy metabolism and located far away from DNA and outside of the cell nucleus, could become subverted to make a substance that poisons the genome,” said Melnick.

“Our study shows for the first time that metabolic enzymes not only help to fuel tumour growth but when mutated can also directly ‘rewrite’ the instructions that govern the genome,” he added.

One important implication of this work is that it appears technically feasible to create drugs that can specifically stop mutant IDH1 and IDH2 from making the cancer-causing poison.

Such inhibitors have the potential to fundamentally restore normal functioning to the genome and thus help to treat leukaemias.

The study is published today in the online edition of the journal Cancer Cell. (ANI)