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Protein Associated with Leukemia May Lead to Targeted Therapy for Currently Incurable Acute Lymphoblastic Leukemia

Date:2020-1-14 9:21:01Browse volume:Source of articles:pharmacytimes

Researchers from the University of Zurich and the University Children’s Hospital Zurich have found a way to stop the driving force, at a molecular level, behind acute lymphoblastic leukemia (ALL), the most common form of cancer affecting children in Switzerland. Their research also allowed them to develop a method of targeted therapy for the disease.

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ALL is a form of blood cancer that primarily affects children and young people and causes large quantities of malignant progenitor cells to build in a patient’s blood instead of healthy white blood cells. This is often caused by 2 chromosomes fusing together to create new abnormal genes that disrupt the system controlling normal blood development. Because of this process, certain types of leukemia are extremely resistant and unable to be cured with intensive chemotherapy or stem cell transplantation.

Researchers analyzed a protein called TCF3-HLF, which is typically associated with this type of leukemia and does not occur naturally. It is produced through the fusion of 2 chromosomes and contains elements of transcription factors, which activate the transcription of certain genes.

The analysis revealed that TCF3-HLF activates a whole range of genes, but it does so in the wrong context—at the wrong point in the blood development process. The formation of malignant white blood cells is then triggered, causing leukemia.

The study authors also discovered that the abnormal protein does not act alone, but instead gathers more than 100 other proteins around it, which helps to activate the genes. The researchers investigated the function of the individual proteins in the genetic machinery and used it to identify key elements that could be targeted through therapy.

Using the CRISPR/Cas9 method, researchers detached the specific parts they had identified from the machinery and found 11 critical factors that are crucial to the build-up of malignant abnormal blood cells in leukemia.

One of the essential components now identified is the protein EP300, a cofactor that boosts gene activation. The researchers used a new kind of substance called A-485, known to bind to EP300 and inhibit its activity. When A-485 was administered to human leukemia cells, the malignant cells died off.

The study authors noted that it is possible to stop the fundamental driving force behind the leukemia directly and thus develop a targeted type of therapy. Given that other forms of leukemia are caused by similar mechanisms, it may also be possible to identify a common denominator for developing new drugs to combat cancer.


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