Targeting a pathway essential for the survival of certain types of acute myeloid leukemia could offer a new therapeutic path for patients, according to the latest research.
Researchers at the Wellcome Sanger Institute have found that a specific genetic mutation, which is linked to a poor prognosis for blood cancer, is involved in the development of the disease when combined with other mutations in mice and human cell lines.
The study, published today (April 30) in Nature communications, allows us to better understand how the loss of function mutation in the CUX1 gene leads to the development and survival of acute myeloid leukemia. The results suggest that targeting a pathway that is essential for these cancer cells to continue to grow could lead to new targeted therapies for some patients.
Acute myeloid leukemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy and prolonged hospital stays. It usually grows in bone marrow cells to crowd out healthy cells, in turn leading to life-threatening infections and bleeding. Traditional treatments for AML have remained unchanged for decades and less than one in three people survive cancer.
Previously, through large-scale DNA sequencing analysis, researchers at the Wellcome Sanger Institute found that loss-of-function mutations in the CUX1 gene on chromosome 7q has been observed in several types of cancer, including AML, where it is associated with a poor prognosis. However, the role of this gene in the development of AML is not clear.
In this new study, the team used CRISPR / Cas9 gene editing technology to show that the lack of functioning CUX1 leads to the expansion of certain types of blood stem cells, which are defective in a type of regulated cell death called apoptosis. They found that the loss of CUX1 causes increased expression of CFLAR gene – which encodes a protein that limits apoptosis – potentially providing a way for mutated cancer cells to escape cell death and spread. Researchers have shown that targeting CFLAR, or apoptosis escape routes in general, may be a possible treatment for those living with this type of AML which is linked to a poor prognosis. Currently, there are no clinically approved drugs that target CFLAR.
Dr Saskia Rudat, co-first author and postdoctoral researcher at the Wellcome Sanger Institute, said: “In studying the role of CUX1 In addition, we now have new knowledge about how this gene, and its absence when mutated, plays a key role in the survival of cancer cells in the blood. Although this mutation does not appear to cause the development of a malignant disease on its own, focusing on the pathways involved CUX1 is a good target for further research. “
Dr Emmanuelle Supper, co-first author and postdoctoral researcher at the Wellcome Sanger Institute, said: “Building on our previous analysis, this research has provided us with crucial information on the development of this disease, and would not have been possible without the new and exciting CRISPR / Cas9 and genome sequencing technologies that allow us to study the genetic weaknesses of cancer.Learn more about the genetic basis of the disease and how multiple mutations combine to cause cancer of the blood is vital if we hope for the future. “
Dr Chi Wong, senior author and Wellcome Clinical Fellow at the Wellcome Sanger Institute and Honorary Consultant Hematologist at Addenbrooke Hospital, said: “Acute myeloid leukemia is a devastating disease, which is currently difficult to treat. especially in cases characterized by genetic lesions such as loss of CUX1 and deletions of chromosome 7q. This new study provides evidence that could be used to help develop a new targeted treatment for some people with acute myeloid leukemia, offering hope for this group of patients who, unfortunately, are more likely to have a poor prognosis. . “
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