A new approach in leukemia research: Glucose deprivation stops malignant transformation of blood cells

An excessive proliferation of immature blood cells is a hallmark of leukemia. This often occurs as a result of a genetic rearrangement that leads to gene fusion and alters the function of the genes in question. In addition, the uncontrolled blood cell growth requires a lot of energy, most of which is provided by glycolysis. Nobel Prize winner Otto Warburg first discovered the special characteristics of cancer cell metabolism back in 1930. Since then, energy generation from glucose in tumors without the use of oxygen has been referred to as the Warburg Effect.

In a research project funded by the Wilhelm Sander Foundation, research groups led by Philipp Greif and Christian Wichmann from the LMU hospital in Munich and the German Cancer Consortium (DKTK) have now been able to inhibit the proliferation of immature blood cells, which are a precursor to leukemia, through a targeted intervention in their metabolic pathway, and have shown that the loss of function of a particular gene leads to an increased glucose dependency in leukemia cells. Their research findings were published in the influential Oncogene journal on March 2, 2020 (Redondo Monte et al. Oncogene, 2020 Mar 2, epub ahead of print).

In some leukemia patients, particularly those with a form of acute myeloid leukemia (AML), blood cell mutation is initially triggered by a certain type of gene fusion. To investigate the effects of this on cell growth in more detail, the scientists used human blood stem cells from healthy donors and introduced the gene fusion artificially. The researchers observed that the modified cells multiplied significantly over a period of one to two months in the culture dish, displacing the untreated cells.

In leukemia cells, this gene fusion frequently occurs in combination with another defect in a gene known as ZBTB7A, which regulates glycolysis in healthy cells. So, in a next step, the researchers also inserted an intact ZBTB7A gene into the immature blood cells in order to hinder the energy supply to the cancer cells and slow down their proliferation. However, when the scientists used an inactive form of ZBTB7A in the experiment, the blood cells continued to proliferate unchecked. In the future, it may be possible to use this mechanism therapeutically: if genetic scissors are used to switch off the genetic function of ZBTB7A in leukemia cells with an intact form of this gene, the cells are able to metabolize more glucose and their glucose requirement increases as a result. At the same time, these cells become more sensitive to the administration of an inhibitor, a modified glucose molecule. This, in turn, can be used to block glycolysis in the leukemia cells artificially, thereby inhibiting their growth. These research findings are also relevant for other diseases, such as colon cancer, for instance, in which the loss of ZBTB7A function can also facilitate the growth of solid tumors.

In addition, the experiments showed that ZBTB7A also regulates the development of healthy blood cells and can influence lipid metabolism. Not much is known about the interplay between metabolism and hematopoiesis. The aim now is to research the underlying molecular mechanisms in more detail.

Original publication: Redondo Monte E, et al., ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells. Oncogene 2020 Mar 2. doi: 10.1038/s41388-020-1209-4.