Study reveals new mechanism by which leukemia cells exploit cellular recycling process – A recent study led by Professor Stefan Müller from Goethe University’s Institute of Biochemistry II has shed light on a new mechanism by which leukemia cells exploit the cellular recycling process to their advantage. The study focused on acute myeloid leukemia (AML), a blood cancer that mainly affects adults and often proves fatal for older patients. In about a third of AML cases, the cancer cells harbor a characteristic mutation in the NPM1 gene, which leads to a mutated form of the NPM1 protein (NPM1c).
While the importance of NPM1c in AML development was previously known, the researchers have now uncovered a novel way in which it contributes to the disease. They found that NPM1c interferes with autophagy, a crucial cellular process that allows cells to recycle their own components. This “self-digestion” serves two main purposes:
- Removal of defective molecules
- Production of essential building blocks, particularly under nutrient deficiency or increased cell proliferation (a hallmark of cancer cells)
During autophagy, the cell first creates a “waste bag” called an autophagosome, which engulfs cellular components destined for breakdown and recycling. This waste bag is then transported to the cell’s recycling center, the lysosome, where its contents are broken down using acid and enzymes. The resulting building blocks are then released back into the cell for reuse.
“We have now been able to show that NPM1c promotes the production of both autophagosomes as well as lysosomes,” says Müller. The researchers discovered that NPM1c achieves this by binding to GABARAP, a key regulator of the autophagosome-lysosome system, and activating it.
“Using computer simulations, we have shown that this binding of NPM1c and GABARAP has an atypical structure,” explains study co-author Dr. Ramachandra M. Bhaskara. Furthermore, experimental structural biology data confirmed the simulation results. This new understanding of the interaction between NPM1c and GABARAP opens up exciting possibilities for developing drugs that specifically target this binding and potentially combat the growth of leukemia cells.
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Key points of the study:
- NPM1c, a mutated protein found in about a third of AML cases, promotes the production of autophagosomes and lysosomes.
- NPM1c binds to and activates GABARAP, a key regulator of the autophagosome-lysosome system.
- This interaction has an atypical structure that could be exploited for developing new AML treatments.
Potential implications:
- The findings could lead to the development of novel, targeted therapies for NPM1c-positive AML.
- Understanding the role of NPM1c in autophagy could provide insights into other diseases associated with this cellular process.
Further research is needed:
- To validate the findings in larger clinical studies.
- To develop and test NPM1c-GABARAP binding inhibitors as potential AML therapies.
- To explore the potential role of NPM1c in other diseases associated with autophagy.
This new discovery is a significant step forward in our understanding of AML and could pave the way for the development of more effective treatment options for patients with this devastating disease.
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