Misregulated protein breakdown promotes leukemias and brain cancer

November 9, 2017, German Cancer Research Center

An enzyme that is responsible for the breakdown of specific amino acids in food plays a key role in the development of leukemias and brain cancer, according to scientists from the German Cancer Research Center (DKFZ) in Heidelberg. They have reported their findings in Nature. The researchers have discovered a surprising link between energy metabolism and the so-called epigenetic code. These labels in the DNA of cancer stem cells determine the activity of genes, and thus, many cellular functions. The authors think that blocking this enzyme is a promising approach to combat cancer.

Acute myeloid leukemia (AML) is an aggressive type of blood that very often relapses in the wake of successful initial treatment. Stem cells that are resistant to therapy are believed to be responsible. Scientists working with Andreas Trumpp from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and HI-STEM wanted to understand the molecular background to this resistance. To this end, they examined patient samples by comparing the composition of proteins of AML stem cells and leukemia cells without stem cells properties.

The investigators found suspiciously high levels of an enzyme called BCAT1 in the stem cells. These levels rose even higher during a cancer recurrence. The researchers considered this to be a clue that BCAT1 might be linked to therapy resistance. Cancer researchers have suspected for some time that the BCAT1 enzyme, which is responsible for the breakdown of specific proteins in food, plays a role in the development of malignant tumors. A team led by Bernhard Radlwimmer from DKFZ had recently found that an overproduction of BCAT1 increases the aggressiveness of and breast cancer.

The two research groups have now joined forces in order to find out how BCAT1 influences the therapy resistance of . They discovered a previously unknown process in which a key molecule of plays a crucial role. BCAT1 reduces the levels of this key molecule and this leads to increased levels of chemical labels in the DNA.

"These tiny methyl groups that are attached to DNA determine whether particular genes are active or silent and, thus, have an immense impact on all ," said Simon Raffel, one of the study's first authors.

This result was notable, because in another 30 percent of AML cases, defects in other enzymes lead to the same consequence: They increase cancer-promoting methylation of DNA. AML is known for an extremely heterogeneous pattern of genetic alterations. However, misregulated methylation with its drastic consequences for the whole cell appears to be a common characteristic of this malignant disease.

The finding that BCAT1 drives cancer-promoting methylation in AML stem cells and other cancer opens up new options for therapy: "A blockade of the enzyme using a targeted agent might normalize DNA methylation and thereby reduce cancer spread and therapy resistance," Trumpp said.

Explore further: Researchers harness metabolism to reverse aggressiveness in leukemia

More information: Simon Raffel et al, BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation, Nature (2017). DOI: 10.1038/nature24294

Related Stories

Researchers harness metabolism to reverse aggressiveness in leukemia

May 17, 2017
University of Georgia researchers, with colleagues from the University of Tokyo, have identified a new drug target for the two most common types of myeloid leukemia, including a way to turn back the most aggressive form of ...

Brain cancer: Hunger for amino acids makes it more aggressive

June 24, 2013
An enzyme that facilitates the breakdown of specific amino acids makes brain cancers particularly aggressive. Scientists from the German Cancer Research Center discovered this in an attempt to find new targets for therapies ...

Blocking cancer-specific mutations in leukemia and brain tumors

May 30, 2017
The substitution of a single amino acid in a metabolic enzyme can be the cause of various types of cancer. Scientists from the German Cancer Research Center and Heidelberg University Hospital, collaborating with Bayer AG, ...

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

July 19, 2017
Glioblastoma is a malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein ...

Stop signal for leukemia stem cells

August 23, 2011
There are numerous specialized growth factors that are responsible for cells of different tissues of our body to divide and differentiate when needed. These hormone-like factors bind to matching receptors on the surface of ...

Recommended for you

Single-cell study in a childhood brain tumor affirms the importance of context

April 20, 2018
In defining the cellular context of diffuse midline gliomas, researchers find the cells fueling their growth and suggest a potential approach to treating them: forcing their cells to be more mature.

Aggressive breast cancer already has resistant tumour cells prior to chemotherapy

April 20, 2018
Difficult to treat and aggressive "triple-negative" breast cancer is chemoresistant even before chemotherapy begins, a new study by researchers from Karolinska Institutet and the University of Texas MD Anderson Cancer Center ...

Mechanism that drives development of liver cancer brought on by non-alcoholic fatty liver disease discovered

April 19, 2018
A team of researchers from several institutions in China has found a mechanism that appears to drive the development of a type of liver cancer not caused by alcohol consumption. In their paper published in the journal Science ...

Discovery adds to evidence that some children are predisposed to develop leukemia

April 19, 2018
St. Jude Children's Research Hospital researchers have made a discovery that expands the list of genes to include when screening individuals for possible increased susceptibility to childhood leukemia. The finding is reported ...

Chip-based blood test for multiple myeloma could make bone biopsies a relic of the past

April 19, 2018
The diagnosis and treatment of multiple myeloma, a cancer affecting plasma cells, traditionally forces patients to suffer through a painful bone biopsy. During that procedure, doctors insert a bone-biopsy needle through an ...

Scientists identify 170 potential lung cancer drug targets using unique cellular library

April 19, 2018
After testing more than 200,000 chemical compounds, UT Southwestern's Simmons Cancer Center researchers have identified 170 chemicals that are potential candidates for development into drug therapies for lung cancer.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.