New therapeutic target for treating AML
Acute myeloid leukemia (AML) is a fast-growing cancer of the myeloid line of blood cells. Most AML patients who achieve complete remission after initial treatment will eventually relapse. That's what makes the disease so hard to handle.
A team of researchers from Germany and Israel set out to address this question. Published online 8 November 2017 in the journal Nature, their study provides a new therapeutic target to compromise leukemia stem-cell function in certain patients.
Growing evidence supports a critical role of cancer stem cells in the development of drug resistance, metastasis, and relapse. The team compared the protein composition of cancer cells with or without stem cell properties in samples from AML patients, with the help of high-resolution proteomic techniques. They discovered that AML stem-cell population had increased BCAT1 protein, which is an enzyme critical for the breakdown of essential branched-chain amino acids (BCAA), and enhanced BCAA pathway.
Recent studies have linked the BCAA pathway and high BCAT1 levels to cancer aggressiveness. Bernhard Radlwimmer, a co-lead researcher of the new study who is from German Cancer Research Center (DKFZ), previously found that BCAA catabolism had an eminent role in glioblastoma, and silencing of BCAT1 significantly reduced breast tumor volume in mice. The evidence indicates that BCAT1 overexpression could contribute to the aggressiveness of these cancers. But the precise mechanisms have not been completely elucidated.
In this work, the team identified BCAT1 as a critical regulator of intracellular α-ketoglutarate (αKG) homeostasis. αKG is an important biological compound and is an intermediate in the energy production process -- the citric acid cycle (CAC). The team found that BCAT1 knockdown in leukemia cells triggered αKG accumulation, eventually impairing the ability of cancer cells to grow, survive, and initiate novel cancer formation. In contrast, BCAT1 overexpression in leukemia cells led to reduced intracellular αKG levels and triggered DNA hypermethylation, which altered gene expression in a way that could promote cancer development.
Taken together, the results suggest that BCAT1 overexpression could cause cancer-promoting methylation in AML cells. Therefore, drugs that block BCAT1 may normalize DNA methylation and prevent cancer progression.