Targeting Genetic Pathway Provides a Novel Treatment for Blood Cancer

Specific genetic mutation has been identified to pose vulnerability in some cases of acute myeloid leukemia and is associated with the poor prognosis of these cancers.

New therapy avenue for certain types of acute myeloid leukemia patients can be designed by targeting a specific pathway that is essential for the survival of these cancers, as per a study at the Wellcome Trust Sanger Institute, published in the journal Nature Communications.

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy and prolonged hospital admissions. It typically develops in cells within the bone marrow to crowd out the healthy cells, in turn leading to life-threatening infections and bleeding.

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‘Specific genetic mutation has been identified to pose vulnerability in some cases of acute myeloid leukemia and is associated with the poor prognosis of these cancers. This suggests that targeting the apoptosis evasion pathway, which is essential for these cancer cells to continue growing, could lead to new targeted therapies for some patients.’

It is found that a specific genetic mutation, which is linked with poor prognosis in blood cancer, is involved in the development of the disease when combined with other mutations in mice and human cell lines.

As the mainstream AML treatments have remained unchanged for decades and fewer than one in three people survives cancer, the study provides a greater understanding of how the loss-of-function mutation in the CUX1 gene leads to the development and survival of acute myeloid leukemia. However, the role of this gene in AML development is unclear.

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The study team utilized CRISPR/Cas9 gene-editing technology to demonstrate that lack of functioning CUX1 leads to expansion of certain types of blood stem cells, which are defective in a type of regulated cell death known as apoptosis.

It was also found that the loss of CUX1 causes increased expression of the CFLAR gene that is responsible for encoding a protein that restrains apoptosis. This potentially provides a means for mutated cancer cells to evade cell death and propagate.

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Thus targeting CFLAR, or apoptosis evasion pathways in general could be a possible treatment for those living with this type of AML that is linked to poor prognosis. Currently, there are no clinically approved drugs that target CFLAR.

Targeting the Apoptosis Evasion Pathway

"By investigating the roles of CUX1 further, we now have new insight into how this gene, and the lack of it when mutated, plays a key role in the survival of blood cancer cells. 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," says Dr. Saskia Rudat, co-first author, and Postdoctoral Fellow at the Wellcome Sanger Institute.

"By building on our previous analysis, this research has allowed us to gain crucial information about the development of this disease, and 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. 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," says Dr. Emmanuelle Supper, co-first author, and Postdoctoral Fellow at the Wellcome Sanger Institute.

The current study thereby provides evidence for the development of new targeted treatment for patients living with acute myeloid leukemia. This offers hope for the group of patients who have a poor prognosis.

Source-Medindia