Targeting Signal Transducer and Activator of Transcription 3 in Acute Myeloid Leukemia: From Oncogenic Mechanisms and Genetic Variants to Therapeutic Inhibition

Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy that is characterized by impaired proliferation and differentiation of hematopoietic stem cells, often leading to poor prognosis. Identifying new therapeutic targets is crucial for improving treatment outcomes. Signal transducer and activator of transcription 3 (STAT3) is a critical oncogene that is implicated in AML. In addition, it is a transcription factor that is activated via phosphorylation by members of the Janus kinase protein family and regulates the expression of several genes involved in oncogenic pathways. This research reviewed studies evaluating the role of STAT3 in AML. This review study investigated over 50 relevant articles focusing on STAT3-related genetic alterations, including mutations (e.g., STAT3-RARα fusion) and single-nucleotide polymorphisms, such as rs1905339 (A>G), rs9909659 (G/A), and rs17886724 (T/C). It also evaluated current experimental and clinical research on STAT3-targeted therapies, including compounds such as trametinib, artesunate, OPB-51602, napabucasin, atovaquone, ortho-topolin, and W1046. STAT3 genomic variations were linked to AML prognosis and disease progression. According to preclinical and clinical studies, inhibiting the expression of STAT3 could impair the survival of AML blasts and improve the prognosis of patients. However, there is currently no approved, effective STAT3-targeting therapy available for AML patients. Overall, STAT3 dysfunction plays a pivotal role in the progression of AML. Nonetheless, further investigations into STAT3-targeted therapies may lead to the development of effective compounds, offering improved prognosis and treatment strategies for AML patients.

Keywords: Acute myeloid leukemia, STAT3, Pathogenesis, Mutation, Polymorphism, Clinical effects