In a recent study, scientists led by Professor Stefan Müller from Goethe University’s Institute of Biochemistry II investigated a specific form of blood cancer known as acute myeloid leukemia, or AML. The disease occurs mainly in adulthood and is often fatal for elderly patients. In about a third of AML patients, the genetic material of the cancer cells has a characteristic mutation that affects the so-called NPM1 gene, which contains the structural instructions for a protein of the same name.
While it was already known that the mutated variant NPM1 (abbreviated as NPM1c) is an important factor in the development of leukemia, “together with an interdisciplinary team consisting of various research groups at Goethe University, we have now discovered a new way in which the NPM1c gene variant it does that,” explains Müller. According to this, the modified protein interferes with autophagy, an important cellular process consisting of a metabolic pathway through which the cell recycles its own structures. On the one hand, this “autodigestion” serves to remove defective molecules. “On the other hand, it also allows the cell to meet its need for important structural elements, including nutrient deficiency or increased cell proliferation, which is characteristic of cancer cells,” explains PhD student Hannah Mende, first author of the study. .
During autophagy, the cell first produces a kind of garbage bag, the autophagosome, in which it packages those cellular components that are to be broken down and recycled if necessary. This bag of waste is then transported to the cell’s recycling center, the so-called lysosome, where its contents are broken down with the help of acid and enzymes. From here, the building blocks are then released into the cell, where they can be reused. “We have now been able to show that NPM1c promotes the production of both autophagosomes and lysosomes,” says Müller.
The researchers also provided an answer to the question of how NPM1c mediates these effects: It binds to a central regulator of the autophagosome-lysosome system called GABARAP and thus activates it. “Using computer simulations, we showed that this connection of NPM1c and GABARAP has an atypical structure,” explains study co-author Dr. Ramachandra M. Bhaskara, head of the Institute of Biochemistry II’s Computational Cell Biology Working Group. Experimental structural biology data confirm the simulation results, on the basis of which it may now be possible to develop agents that specifically affect the binding of NPM1c to GABARAP and thus combat the growth of leukemia cells.