JAK/STAT in leukemia: a clinical update

Abstract

Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.

Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review)

“…These inhibitors are tofacitinib, baricitinib, delgocitinib, peficitinib, ruxolitinib, upadacitinib, filgotinib and abrocitinib. Several JAK inhibitors, including the aforementioned eight inhibitors, are in clinical trials to evaluate their efficacy and safety in leukemia ( 242 ) and solid tumors. However, no JAK inhibitors are currently approved to treat these diseases.…”

Hallmarks of cancer resistance

“…In cancer, the dysregulation of the JAK/STAT pathway contributes to both tumor promotion and suppression, making its role in cancer biology complex. 130 Aberrant activation of the pathway is often observed in various cancers, resulting in the constitutive activation of downstream targets that promote cell survival, proliferation, and angiogenesis, fostering tumor growth. Genetic alterations, such as mutations or amplifications in JAK and STAT genes, can lead to persistent pathway activation, facilitating tumorigenesis.…”

The Role of the JAK–STAT Pathway in Childhood B-Cell Acute Lymphoblastic Leukemia

“…Targeting JAK proteins, which initiate the activation of transcription regulators, holds promise for achieving improved therapeutic outcomes and potentially reducing treatment-related side effects in patients. The effect exerted by JAK inhibitors on cells is to block the active sites of kinases, which prevents proper signal transduction and abolishes the effects caused by cytokines [114].…”

“…The therapeutic potential of JAK inhibitors has been substantiated by ex vivo studies on cell lines, demonstrating that inhibiting JAK and thereby preventing STAT activation leads to restricted cell development and increased apoptosis [114,115].…”

“…For this reason, research has begun on STAT inhibitors that may target the SH2 domain, mRNAbinding domain or DNA-binding domain. Currently, the only FDA-approved agent for the leukemia treatment is a STAT1 inhibitor, a purine analogue called fludarabine [114,125]. This drug is administered intravenously in the form of a monophosphate prodrug (F-ara-AMP), which is quickly converted into an intracellularly distributed metabolite: F-ara-A.…”