Age‐associated myeloid malignancies – the role of STAT3 and STAT5 in myelodysplastic syndrome and acute myeloid leukemia

In the last few decades, the increasing human life expectancy has led to the inflation of the elderly population and consequently the escalation of age-related disorders. Biological aging has been associated with the accumulation of somatic mutations in the Hematopoietic Stem Cell (HSC) compartment, providing a fitness advantage to the HSCs leading to clonal hematopoiesis, that includes non-malignant and malignant conditions (i.e. Clonal Hematopoiesis of Indeterminate Potential, Myelodysplastic Syndrome and Acute Myeloid Leukemia). The Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a key player in both normal and malignant hematopoiesis. STATs, particularly STAT3 and STAT5, are greatly implicated in normal hematopoiesis, immunity, inflammation, leukemia, and aging. Here, the pleiotropic functions of JAK-STAT pathway in age-associated hematopoietic defects and of STAT3 and STAT5 in normal hematopoiesis, leukemia, and inflammaging are reviewed. Even though great progress has been made in deciphering the role of STATs, further research is required to provide a deeper understanding of the molecular mechanisms of leukemogenesis, as well as novel biomarkers and therapeutic targets for improved management of age-related disorders.