Scientists discover new mechanism by which leukemia cells exploit cell recycling process
Tue , +08:00 December 05 , 2023
In a recent study, scientists led by Professor Stefan Müller from the Institute of Biochemistry II at Goethe University studied a specific form of blood cancer called acute myeloid leukemia (AML). The disease occurs primarily in adulthood and is often fatal in older patients. In about one-third of AML patients, the cancer cells' genetic material has characteristic mutations affecting a gene called NPM1, which contains the instructions for building a protein of the same name.
While it is well known that mutated NPM1 variants (abbreviated NPM1c) are an important factor in the development of leukemia, "Together with an interdisciplinary team of various research groups at Goethe University, we have now discovered a new way in which NPM1c gene variants can Do that,” Mueller explained. According to this, the altered protein intervenes in autophagy, an important cellular process consisting of metabolic pathways by which cells recycle their own structures. On the one hand, this "self-digestion" removes defective molecules. "On the other hand, it also enables the cell to meet its needs for important building blocks, including in situations of nutrient deficiency or increased cell proliferation, which is required by cancer cells," explains PhD student Hannah Mende, first author of the study. Characteristics." .
During autophagy, cells initially produce waste bags called autophagosomes into which cellular components that need to be broken down and recycled are stored. This waste bag is then transported to the cell's recycling centers, so-called lysosomes, where its contents are broken down with the help of acids and enzymes. From here, the building blocks are released into cells where they can be reused. "We have now been able to show that NPM1c promotes the production of autophagosomes and lysosomes," says Müller.
The researchers also answered the question of how NPM1c exerts these effects: It binds to GABARAP, a central regulator of the autophagosome-lysosome system, thereby activating it. "Through computer simulations, we have shown that this combination of NPM1c and GABARAP has an atypical structure," explains study co-author Dr. Ramachandra M. Bhaskara, leader of the Computational Cell Biology Working Group at the Institute of Biochemistry. Experimental structural biology data corroborate the simulation results, based on which it is now possible to develop active substances that specifically affect the binding of NPM1c to GABARAP and thereby combat the growth of leukemia cells.