Acute myeloid leukemia (AML) is a myeloid-progenitor-derived neoplasm of poor prognosis, particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies. Around half the patients under the age of 60 die. For that reason there is an increased need for novel therapeutic approaches.
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a kinase that promotes catabolism, represses anabolism, and enhances autophagy in response to stress.
In a recently published study, researchers from the University of Geneva, Switzerland, and from Inserm, in France, have identified a previously unknown mechanism that could lead to the development of new therapies.
New Study Findings
The researchers found that the selective activation of AMPK, a key enzyme in the energy balance of tumor cells, would indeed lead to their death by triggering the cell’s stress response.
The researchers used an animal model of the disease to exploit this energy gap. A combination of 2 drugs has shown promise. However their effectiveness hasn’t been confirmed on leukemia stem cells.
The researchers identified an enzyme, PERK, that was particularly activated in response to the presence of GSK621, which is a key element in the stress response of the endoplasmic reticulum. The activation of AMPK triggers the activation of PERK, which leads to a chain of reactions that end in apoptosis (programmed cell death). This activation of AMPK also sensitizes the cells to the effects of the drug venetoclax, commonly used to treat AML.
The researchers combined the 2 drugs in mice carrying human tumor cells, and found that this controlled tumor development more effectively than using one medication alone.
The findings of the study could help develop new drugs that could activate the AMPK pathway and hopefully increase the survival rate of AML in elderly patients.
Emily Henderson, B. Sc. (2022, Feb 17). Combating leukemia cells by disrupting their energy maintenance mechanism. News Medical Life Sciences. Retrieved from:
Grenier, A., et al. (2022) AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia. Cell Reports. doi.org/10.1016/j.celrep.2021.110197.