Leukaemia enzyme identified as drug target

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Scientists have identified an enzyme that helps trigger the
development of leukaemia. The discovery, based on research using
bone marrow cells from mice, offers a potential target for new
drugs against this form of leukaemia.

The enzyme, called hDOT1L, activates a set of genes that plays a key role in the rare and largely incurable acute myeloid leukaemia (AML). The research has suggested that this enzyme helps transform, or immortalise, bone marrow cells, causing their unrestrained growth, a hallmark of leukaemia. This disease affects less than 2 per cent of the estimated 16,000 individuals diagnosed with acute leukaemia nationwide each year.

Dr Yi Zhang, lead researcher of this study, investigated a group of enzymes that modifies five core histone proteins forming the molecular scaffold that helps organise DNA within the nucleus of every cell. Histone modifications affect gene activity and include methylation, in which a methyl component is attached to the histone protein.

As an enzyme that adds a methyl component to histone H3, hDOT1L activates the gene associated with that histone. Zhang and fellow researchers now provide evidence that in some leukaemias, hDOT1L activates so-called Hox genes, whose increased activity is closely tied to AML.

"We demonstrate that not only is hDOT1L required for transformation of bone marrow cells, but, more importantly, that its enzymatic activity is required to maintain the transformed status,"​ said Zhang. "That means if we have a way to prevent the activity of hDOT1L, then the affected cells of particular leukaemia patients can be killed."

Leukaemia most often arises from a chromosomal translocation, a breaking and joining of two distinct chromosomes, that creates a hybrid gene. The product of the hybrid gene is called a "fusion protein," meaning that the newly formed gene encodes a protein made of fragments from each of the two genes that were fused together by the rearrangement.

"The prevailing model is that methylation on histones serves as a docking site,"​ Zhang said. "It will recruit proteins that 'read' this histone modification, and it's those proteins that directly have an impact on gene expression - either activating or silencing a gene."

Some leukaemia patients carry rearrangements of a gene on chromosome 11 called the mixed lineage leukaemia gene, or MLL. Translocations involving MLL are most often found in childhood leukaemia and as a secondary cancer in adults who have undergone chemotherapy to treat a previous leukaemia.

Individuals with MLL translocations have an especially poor prognosis, with less than a 50 per cent survival rate.

"There are more than 40 proteins that have been found fused to MLL in leukaemia patients, and different ones can cause leukaemia by different mechanisms,"​ Zhang said.

When MLL functions as it should, without a fusion partner, it binds to and controls the expression of Hox genes, which in turn control cell growth and maturation. Until now, the role of the MLL-AF10 fusion protein in causing leukaemia was unknown.

"We show how at least one MLL fusion can lead to the over-expression of Hox genes in bone marrow cells. MLL-AF10 directs hDOT1L to the Hox genes, where it normally shouldn't be, causing a different pattern of histone methylation and, therefore, extraordinarily high activity of the Hox genes,"​ Zhang said.

Treatments used for AML patients have been largely ineffective against cells harbouring the MLL-AF10 fusion protein, drawing attention to the need for a new medication.

Zhang's study reveals that leukaemia cells containing MLL-AF10 require hDOT1L to survive. When the researchers introduced into leukaemia cells a defective form of hDOT1L, one that cannot methylate histone proteins, the cells were no longer able to grow.

"This study highlights the potential of hDOT1L as a possible drug target,"​ Zhang added.

The new findings appear in April 21 issue of the journal >Cell.

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