New research in mice indicates a possible targeted therapy for a form of pediatric cancer, acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is a form of blood cancer that primarily affects children and young people. It involves large quantities of malignant progenitor cells building up in a person’s blood instead of healthy white blood cells. This often results from a change in genetic material, with two chromosomes fusing together to create new abnormal genes that disrupt the system controlling normal blood development.
These types of leukemia are often extremely resistant and incurable with intensive chemotherapy or stem cell transplantation.
In search of new ways to tackle this problem, scientists from the University of Zurich and the University Children’s Hospital Zurich have been scrutinizing the molecular causes of this disorder.
Wrong place, wrong time
Study leaders Jean-Pierre Bourquin and Beat Bornhause and colleagues analyzed a protein called TCF3-HLF, which is typically associated with this type of leukemia. This protein does not occur normally; it results from the fusion of two chromosomes and contains elements of what are known as transcription factors, which activate the transcription of certain genes.
Their analysis reveals that the abnormal protein TCF3-HLF also activates a whole range of genes, but it does so in the wrong context and at the wrong point in the blood development process. This triggers the formation of malignant white blood cells and causes leukemia.
“Our research shows that the abnormal protein binds to almost 500 regulatory elements in the genetic material of the human leukemia cells, activating hundreds of genes by mistake,” explains Yun Huang, lead author of the study in Cancer Cell.
The researchers also discovered that the abnormal protein gathers more than 100 other proteins around it, which help to activate the genes.
“We investigated the function of the individual proteins in this genetic machinery and used this to identify key elements that could be targeted through therapy,” explains Huang.
Using the ‘gene cutter’ against acute lymphoblastic leukemia
He and his colleagues used the CRISPR/Cas9 method, sometimes referred to as a “gene cutter,” to detach the specific parts they had identified from the machinery. As a result, they found eleven critical factors that are crucial to the build-up of malignant abnormal blood cells behind leukemia.
One of the essential components now identified is the protein EP300, a cofactor that boosts gene activation. An experiment with mice indicated that EP300 could be a very promising target for therapy. For this investigation, the researchers used a new kind of substance called A-485, which is known to bind to EP300 and inhibit its activity. When A-485 was administered to mice carrying human leukemia cells, the malignant cells died off.
“It is therefore possible, in principle, to stop the fundamental driving force behind this leukemia directly and thus develop a targeted type of therapy,” says Bourquin. “The important thing now is to build a fuller picture of what goes wrong so that we can investigate the best possible way to combine specific modes of attack like this.”
Given that similar mechanisms cause other forms of leukemia, it may also be possible to identify a common denominator for developing new drugs to combat cancer.
The researchers also collaborated with working groups that Marie-Laure Yaspo from the Max Planck Institute for Molecular Genetics in Berlin and Matthias Gstaiger from ETH Zurich led. The project took place as part of the University of Zurich’s Clinical Research Priority Program, “Precision Hematology/Oncology.”
Funding came from Krebsliga Schweiz, the Swiss National Science Foundation, the Childhood Cancer Research Foundation Switzerland, the Empiris Foundation, the Fondation Panacée, Stiftung Krebsforschung Schweiz, and the CRPPs “Human Hemato-Lymphatic Diseases” and “Precision Hematology/Oncology.”
Source: University of Zurich
