Researchers closer to finding treatment for incurable form of blood cancer

Switzerland: An incurable form of blood cancer may soon find its cure, suggests a recent study in the journal Cancer Cell.

According to the study, the researchers have discovered a new approach for the treatment of acute lymphoblastic leukemia (ALL) -- a form of incurable leukemia that primarily affects children and young people.

ALL is often extremely resistant and cannot be cured with intensive chemotherapy or stem cell transplantation. Jean-Pierre Bourquin, University Children's Hospital Zurich, Zurich, Switzerland, and colleagues, in a bid to find the cure, have been scrutinizing the molecular causes of this disorder. They analyzed a protein called TCF3-HLF -- typically associated with ALL. This protein does not occur naturally.

ALL involves building up of large quantities of malignant progenitor cells in a person's blood instead of the healthy white cells. This is caused by a change in genetic material caused by fusing together of two chromosomes to create new abnormal genes that disrupt the process of normal blood development.

TCF3-HLF is produced through the fusion of two chromosomes and contains elements of what are known as transcription factors which activates the transcription of certain genes.

"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, according to the research.

"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.

The abnormal protein is not known to act alone, it gathers more than 100 other proteins which helps to activate the genes. In the study. "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. 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 managed to find eleven critical factors that are crucial to the build-up of malignant abnormal blood cells behind leukemia.

For the investigation, the researchers used a new kind of substance called A-485 which binds to EP300 and inhibits its activity. Protein EP300 is a cofactor that boosts gene activation that could be a very promising target for therapy.

The researchers found that 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 research group leader Jean-Pierre 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 an attack like this." 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.

The study, "The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability," is published in the journal Cancer Cell.

DOI: https://doi.org/10.1016/j.ccell.2019.10.004