The science of gene editing continues to advance with the announcement by researchers from the Wellcome Trust Sanger Institute of a new approach to tackling myeloid leukaemia (AML).

The Cambridgeshire-based Trust and its collaborators have adapted a CRISPR gene editing technique to find new therapeutic targets for the condition. In their research, the team identified a large number of genes that could serve as potential targets for anti-AML treatments and showed how the inhibition of one of them, KAT2A, can destroy AML cells without harming non-leukaemic blood cells.

AML, which crowds out healthy cells in the bone marrow, develops rapidly and interferes with the bone marrow’s ability to make normal blood cells, leading to dangerous infections and bleeding. Fewer than one in three people survive the cancer. The team sought new ways to treat AML and used CRISPR-Cas9 gene-editing technology to screen cancer cells for their vulnerable points.

They refined a CRISPR-Cas9 technique to disrupt all genes in the leukaemia cell genome individually. This allowed them to identify genes whose disruption was harmful to AML cells. Dr Kosuke Yusa, joint project leader from the Sanger Institute, said: “Previous studies showed proof of principle but this is one of the first systematic attempts to identify the genetic vulnerabilities of AML. We have improved and applied CRISPR-Cas 9 technology to look at what actually kills cells. CRISPR is becoming a powerful technique in cancer research because it overcomes some of the limitations of earlier tools.”

The human genome contains about 20,000 genes but by refining CRISPR-Cas9 technology and using it to screen the leukaemia genome the team uncovered about 500 genes that are essential for cancer cell survival, including more than 200 for which drugs could be designed. They say that, whilst a handful of these genes including DOT1L, BCL2 and MEN1 are already established therapeutic targets, most of them are novel and open up many new possibilities for developing effective treatments against the disease.

Dr Konstantinos Tzelepis, a first author on the paper from the Sanger Institute, said: “This is an exciting finding, as KAT2A inhibition worked on a number of primary AML cells with diverse genotypes. Whilst the gene needs to be studied in greater depth to understand its potential for use in the clinic, we show that targeting KAT2A destroyed AML cells in the laboratory while sparing healthy blood cells.” The team validated this finding, by disrupting the KAT2A gene from leukaemia cells in transgenic mice and observing the effect on the cancer. They found that the mice lived longer when the KAT2A gene was disrupted.

Dr George Vassiliou, joint project leader from the Sanger Institute and Consultant Haematologist at Cambridge University Hospitals NHS Trust, said: “This research has led to the identification of many potential gene targets for future AML therapy, which we are making available to other researchers to explore. “Whilst KAT2A inhibition now needs to be investigated as a treatment strategy for acute myeloid leukaemia, there are many more candidates to pursue by the leukaemia research community. Our hope is that this work will lead to more effective treatments against AML that will improve both the survival and the quality of life of patients.”

The work was supported by the Kay Kendall Leukaemia Fund, which was established in 1984 under the will of James Sainsbury CBE and awards grants for research on aspects of leukaemia and related haematological malignancies.