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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.

BackgroundThe simultaneous occurrence of severe atopic dermatitis (AD), vitiligo, and alopecia areata (AA) in a single patient is exceptionally rare and poses a significant therapeutic challenge, as conventional “disease-specific” therapies often yield suboptimal results. Emerging evidence implicates the shared JAK-STAT signaling pathway in the pathogenesis of these conditions, suggesting the potential for a targeted “multi-disease therapy” approach.Case presentationA 57-year-old man presented with severe, treatment-refractory AD, extensive vitiligo, and AA. Following the failure of conventional therapies, treatment with the selective JAK1 inhibitor upadacitinib (15 mg daily) was initiated. A rapid and marked improvement was observed: pruritus subsided within days, AD-related erythema cleared substantially by 15 weeks, complete eyebrow regrowth occurred within months, and significant repigmentation of vitiligo lesions was evident at one-year follow-up. The treatment was well-tolerated.ConclusionThis case suggests that upadacitinib monotherapy may be an effective and well-tolerated option for severe co-existing AD, vitiligo, and AA. It provides clinical evidence supporting the novel “multi-disease therapy” paradigm, which targets common pathogenic pathways rather than individual disease phenotypes, offering a new strategic direction for managing complex immune-mediated comorbidities.

Angiogenesis plays a crucial role during tumorigenesis and much progress has been recently made in elucidating the role of VEGF and other growth factors in the regulation of angiogenesis. Recently, microRNAs (miRNAs) have been shown to modulate a variety of physiogical and pathological processes. We identified a set of differentially expressed miRNAs in microvascular endothelial cells co‐cultured with tumour cells. Unexpectedly, most miRNAs were derived from tumour cells, packaged into microvesicles (MVs), and then directly delivered to endothelial cells. Among these miRNAs, we focused on miR‐9 due to the strong morphological changes induced in cultured endothelial cells. We found that exogenous miR‐9 effectively reduced SOCS5 levels, leading to activated JAK‐STAT pathway. This signalling cascade promoted endothelial cell migration and tumour angiogenesis. Remarkably, administration of anti‐miR‐9 or JAK inhibitors suppressed MV‐induced cell migration in vitro and decreased tumour burden in vivo . Collectively, these observations suggest that tumour‐secreted miRNAs participate in intercellular communication and function as a novel pro‐angiogenic mechanism. Secreted miRNAs are increasingly recognized in multiple biological processes. Here, miR‐9 is shown to be secreted from cancer cells to enhance endothelial recruitment. This contribution to tumour angiogenesis could be amenable for therapeutic intervention.

Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are implicated in the development and progression of various tumors. The aim of this study was to investigate the effects of circ_SMA4 in Gastrointestinal Stromal Tumors (GISTs) malignant progression. Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in GISTs. The effect of circ_SMA4 on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo settings. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_SMA4/miR-494-3p/ KIT axis. The results revealed that circ_SMA4 was significantly upregulated in GISTs, and exhibited high diagnostic efficiency with an AUC of 0.9824 (P < 0.01). circ_SMA4 promoted cell proliferation, invasion, migration, while inhibiting apoptosis in GISTs cells, both in vitro and in vivo. Silencing circ_SMA4 partially inhibited GISTs malignant progression. Additionally, circ_SMA4 acted as a competing endogenous RNA (ceRNA) by targeting miR-494-3p, and KIT was identified as a functional gene for miR-494-3p in GISTs. Furthermore, the results confirmed that circ_SMA4/miR-494-3p/ KIT axis plays a role in activating the JAK/STAT signaling pathway in GISTs. Therefore, for the first time, we have identified and emphasized that circ_SMA4 is significantly upregulated and plays an oncogenic role in GISTs by sponging miR-494-3p to activate the KIT/JAK/STAT pathway. These findings underscore circ_SMA4 may serve as a novel diagnostic biomarker and therapeutic target for GISTs.

Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor‐mediated signaling of multiple cytokines and growth factors, including those with pro‐inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head‐to‐head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long‐term clinical data, and when available, real‐world experience.

In recent years, it has become clear that members of the signal transducer and activator of transcription (STAT) family of genes play an important role in cancer. The STAT family consists of seven genes, STAT1‐4, STAT5A, STAT5B and STAT6, that are involved in regulating cellular proliferation, apoptosis, angiogenesis and the immune system response. Constitutive activation of STAT3, via mutational changes, is important in oncogenesis in both solid and hematopoietic cancers. In the case of hematopoietic neoplasms, STAT3 driver mutations have been described in T‐cell large granular lymphocytic (T‐LGL) leukemia and chronic natural killer lymphoproliferative disorders (CLPD‐NK) and are seen in 30%‐40% of T‐LGL leukemia patients. STAT5B is also mutated in T‐LGL leukemia and CLPD‐NK, but in a much smaller proportion. Here we review past and current research on STAT genes in hematopoietic and solid cancers with emphasis on STAT3 and STAT5B and their roles in the pathogenesis of hematopoietic malignancies, particularly T‐LGL leukemia and CLPD‐NK. Mutations in the STAT family of genes are seen in solid tumors and hematopoietic neoplasms. Here we review the STAT genes and their roles in the pathogenesis of these cancers with emphasis on hematopoietic entities.

Aggressive NK-cell leukemia （ANKL） is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% （14/29） of ANKL patients, while the extracelinlar STAT3 stimulator IL10 was elevated by an average of 56-fold （P 〈 0.0001） in the plasma of all patients examined. Additional frequently mutated genes included TP53 （34%）, TET2 （28%）, CREBBP （21%） and MLL2 （21%）. Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic path- ways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis, Collectively, the JAK-STAT path- way represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/ STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.

Inhibition of immune checkpoint molecules, PD‐1 and CTLA4, has been shown to be a promising cancer treatment. PD‐1 and CTLA4 inhibit TCR and co‐stimulatory signals. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine interferon‐γ (IFNγ) plays an important role in anti‐tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway. Among SOCS proteins, CIS, SOCS1, and SOCS3 proteins can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in terms of their anti‐tumor immunity and potential applications. Inhibition of immune‐checkpoint molecules, PD‐1 and CTLA4, has been shown to be a promising cancer treatment. SOCS proteins are the third immune‐checkpoint molecules that inhibit cytokine signaling. This review is focusing on the mechanism of inhibition of cytokine signaling by CIS, SOCS1 and SOCS3, and their relationship to T cell biology and anti‐tumor immunity.

Natural killer (NK) cells were so named for their uniqueness in killing certain tumor and virus-infected cells without prior sensitization. Their functions are modulated in vivo by several soluble immune mediators; interleukin-15 (IL-15) being the most potent among them in enabling NK cell homeostasis, maturation, and activation. During microbial infections, NK cells stimulated with IL-15 display enhanced cytokine responses. This priming effect has previously been shown with respect to increased IFN-γ production in NK cells upon IL-12 and IL-15/IL-2 co-stimulation. In this study, we explored if this effect of IL-15 priming can be extended to various other cytokines and observed enhanced NK cell responses to stimulation with IL-4, IL-21, IFN-α, and IL-2 in addition to IL-12. Notably, we also observed elevated IFN-γ production in primed NK cells upon stimulation through the Ly49H activation receptor. Currently, the fundamental processes required for priming and whether these signaling pathways work collaboratively or independently for NK cell functions are poorly understood. To identify the key signaling events for NK cell priming, we examined IL-15 effects on NK cells in which the pathways emanating from IL-15 receptor activation were blocked with specific inhibitors. Our results demonstrate that the PI3K-AKT-mTOR pathway is critical for cytokine responses in IL-15 primed NK cells. Furthermore, this pathway is also implicated in a broad range of IL-15-induced NK cell effector functions such as proliferation and cytotoxicity. Likewise, NK cells from mice treated with rapamycin to block the mTOR pathway displayed defects in proliferation, and IFN-γ and granzyme B productions resulting in elevated viral burdens upon murine cytomegalovirus infection. Taken together, our data demonstrate the requirement of PI3K-mTOR pathway for enhanced NK cell functions by IL-15, thereby coupling the metabolic sensor mTOR to NK cell anti-viral responses.

Alzheimer’s disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer’s disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer’s disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer’s disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer’s disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer’s disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer’s disease.