Selenoproteins in myeloid lineage and acute myeloid leukemia: targeting new vulnerabilities a narrative minireview

Selenium is a nonmetal element incorporated into a small subset of proteins as selenocysteine, the 21st amino acid. In humans, the so-called selenoproteins represent a unique and physiologically important family of proteins, some of which are essential to life, primarily through the maintenance of redox balance. Other selenoprotein functions include defense against various forms of oxidative stress, thyroid hormone metabolism, muscular homeostasis and integrity, as well as immune regulation, inflammatory responses, and protection against oxidative stress-mediated cell deaths. Increasing evidence shows that inhibiting global selenoprotein expression or targeting individual selenoproteins, such as glutathione peroxidase 4 and thioredoxin reductase 1, can greatly affect cellular redox status in different tissues and organs and trigger cell death through apoptosis, pyroptosis, ferroptosis, or even cuproptosis. This is particularly true in hematopoietic cells, where oxidative stress and reactive oxygen species production may profoundly alter differentiation of stem and lineage-committed progenitor cells and thus contribute to the progression and treatment resistance of hematopoietic malignancies. Thus, inhibition of selenoprotein synthesis or activity by genetic or pharmacological approaches has been shown to trigger apoptosis and/or ferroptosis, leading to the elimination of leukemic cells. Of note, glutathione peroxidases 1 and 4, SELENOM, SELENOO, and SELENOW are overexpressed in some subtypes of acute myeloid leukemia, often conferring a pejorative prognosis. Thus, targeting selenoproteins, either alone or in combination with conventional or targeted therapies, might represent an attractive strategy for the management of patients suffering leukemia.