German scientists have reported a research breakthrough into a gene mutation involved in the development of acute myeloid leukaemia (AML).
Professor Stefan Müller of Goethe University, Frankfurt, Germany and colleagues investigated the characteristic mutation of the NPM1 gene called NPM1c, seen in about a third of AML patients.
They hope their findings could lead to new treatments to block the spread of cancer cells.
In lab experiments, the team has now found that the variant is involved in autophagy, the process of a cell recycling its own structures under starvation conditions.
NPM1c appears to enhance this process by increasing the production of autophagosomes which contain broken down cell pieces, and lysosomes which recycle the pieces into new structures. This supports new cell proliferation, characteristic of cancer cells, the researchers reported.
“Together with an interdisciplinary team consisting of various Goethe University research groups, we have now discovered a new way in which the NPM1c gene variant does this,” Dr Müller said.
“We have now been able to show that NPM1c promotes the production of both autophagosomes as well as lysosomes.”
Looking in further detail, the team found that NPM1c binds to and activates a central regulating protein of the autophagosome-lysosome system called GABARAP.
Co-author Dr Ramachandra Bhaskara said: “Using computer simulations, we have shown that this binding of NPM1c and GABARAP has an atypical structure.”
The researchers believe it may be possible to create substances to limit the binding of NPM1c to GABARAP, and hold back the proliferation of AML cells.
Mende H, Khatri A, Lange C, Poveda-Cuevas SA, Tascher G, Covarrubias-Pinto A, Löhr F, Koschade SE, Dikic I, Münch C, Bremm A, Brunetti L, Brandts CH, Uckelmann H, Dötsch V, Rogov VV, Bhaskara RM, Müller S. (2023) “An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant.” Cell Reports, doi: 10.1016/j.celrep.2023.113484
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