Targeting mitochondrial dysfunction in myeloproliferative neoplasms: current strategies and future directions - a...

Myeloproliferative neoplasms (MPNs) are a group of blood cancers characterized by the clonal proliferation of hematopoietic stem cells. These diseases are driven by acquired genetic mutations that activate the JAK-STAT signaling pathway, leading to abnormal cell proliferation and differentiation. Dysfunction of mitochondria, involving increased production of reactive oxygen species (ROS), mutations within its DNA, and alterations in its dynamics, significantly contributes to the development and progression of MPNs. This dysfunction promotes clonal expansion of abnormal blood cells and hinders their programmed cell death (apoptosis). However, targeting mitochondrial pathways offers a promising therapeutic approach. For instance, strategies that include the use of mitochondria-targeted antioxidants to counteract oxidative stress, inhibitors of mitochondrial metabolism to disrupt energy production in MPN cells, and interventions that modulate mitophagy (the process of removing damaged mitochondria) and mitochondrial dynamics. Indeed, achieving specific drug delivery, overcoming therapeutic resistance, and minimizing side effects are at the top of the list. This mini-review highlights the promise of innovative therapeutic approaches, such as gene editing technologies and RNA-based therapies, in addressing mitochondrial dysfunction. Furthermore, it underscores the critical importance of personalized medicine strategies in optimizing the efficacy and safety of mitochondrial-targeted treatments. Future research directions encompass further refinement of these strategies, validation of biomarkers for patient selection, and the development of effective combination therapies. By emphasizing the critical role of mitochondrial dysfunction in the pathogenesis of MPNs, this review provides a framework for improving clinical outcomes and developing novel therapeutic strategies that target these underlying metabolic abnormalities.