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Potential genetic target for leukaemia treatment identified

10 May 2021
Appeared in BioNews 1094

The biological mechanism linking a certain gene mutation with poor prognosis in acute myeloid leukaemia (AML) has been discovered. 

AML is an aggressive blood cancer which develops in the bone marrow. According to Cancer Research UK, people diagnosed with AML have a survival rate at five years of approximately 20 percent, and there have been no new mainstream treatments developed in decades.  

'Acute myeloid leukaemia is a devastating disease, which is currently difficult to treat, especially in cases characterised by genetic lesions such as loss of [the gene] CUX1, and chromosome 7q deletions. This new study provides evidence that could be used to help develop new targeted treatment for some people living with acute myeloid leukaemia, offering hope for this group of patients who unfortunately are more likely to have a poor prognosis.' said Dr Chi Wong, senior study author and clinical fellow at the Wellcome Sanger Institute, Cambridge and honorary consultant haematologist at Addenbrooke's Hospital, Cambridge. 

In the recent study, published in Nature Communications, the team used CRISPR/Cas9 screening to isolate CUX1-mutated cancer cells, and also the CRISPR/Cas9 genome editing approach to create CUX1-mutant mice.

The scientists demonstrated that lack of fully-functional CUX1 leads to the multiplication of blood stem cells that do not die when they are programmed to, which is a hallmark of cancer. They also showed that the loss of CUX1 increased expression of the CFLAR gene, which codes for a protein that restricts apoptosis, a cause of cell death. The researchers propose the apoptosis pathway, and the CFLAR protein specifically, as potential new targets for AML treatment. There are currently no clinically approved drugs that target the CFLAR pathway. 

'While this mutation doesn't seem to cause the development of malignant disease on its own, focusing on the pathways involved with CUX1 is a good target for further research,' summarised Dr Saskia Rudat, co-first author and postdoctoral fellow at the Wellcome Sanger Institute.

'[This research] would not have been possible without the new and exciting CRISPR/Cas9 and genome sequencing technologies that enable us to investigate genetic weaknesses in cancer,' said Dr Emmanuelle Supper, also co-first author and postdoctoral fellow at the Wellcome Sanger Institute. She added, 'Understanding more about the genetic basis of disease, and how multiple mutations come together to cause blood cancer is vital if we hope to save lives in the future.'

Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia
Nature Communications |  30 April 2021
New genetic target for blood cancer treatment
Wellcome Sanger Institute |  30 May 2021
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