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PubMed2026

Identifying JAK2 and ANXA5 as Key Genes Linking Obstructive Sleep Apnea and Oxidative Stress via Machine Learning and Multilayer Transcriptomic Integration With Functional Validation.

Obstructive sleep apnea (OSA) is a common and severe sleep disorder closely associated with oxidative stress (OS). This study aims to identify and validate potential OS-related genes associated with OSA through bioinformatics methods. We successfully identified OS-related differentially expressed genes (OS-DEGs) by combining the limma test, weighted correlation network analysis (WGCNA), and OS-related genes from the GeneCards database. Key genes and potential biological roles were further identified using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), enrichment analysis, protein-protein interaction (PPI) network analysis, Lasso regression analysis, random forest algorithm, and support vector machine recursive feature elimination (SVM-RFE) method. Evaluate and validate the accuracy of key genes through receiver operating characteristic (ROC) curve analysis. The human single-cell RNA sequencing (scRNA-seq) dataset is used for cell classification annotation, analysis of key gene single-cell expression profiles, and virtual gene knockout experiments based on the scTenifoldKnk algorithm. Integrating scRNA-seq sequencing, pseudotime trajectory inference, cell-cell communication analysis, and bulk immune infiltration deconvolution reveals monocyte subtype remodeling in OSA. Finally, the expression levels of key genes in clinical samples were validated using real-time quantitative PCR (RT-qPCR) and Western blotting. A total of 57 common DEGs, indicating significant enrichment in OS, inflammation, and tumor pathways, particularly prominent in the immunometabolism pathway. By integrating DEGs, WGCNA, PPI results, and machine learning methods, key genes Janus kinase 2 (JAK2) and ANXA5 were screened out. JAK2 was significantly upregulated under disease conditions, while ANXA5 was significantly downregulated. ROC curve exhibited high accuracy (area under the curve [AUC] > 0.85). Human scRNA-seq analysis revealed that key genes were predominantly highly expressed in monocytes. Virtual knockout experiments demonstrated that these key genes play a crucial role in regulating immune responses and inflammatory reactions. PPI networks and enrichment analysis verified that downstream genes S100P, ALOX5AP, PROK2, and PADI4 may collaboratively participate in immune response and inflammation regulation. Finally, clinical sample experiment further validated the results of bioinformatics analysis. This study provides new research insights for the diagnosis, mechanism research, and treatment development of OSA in the future by integrating multilayer transcriptomic and machine learning techniques.

Humans↗

PubMed2026

Age as a core disease modifier: Distinct clinical, molecular and prognostic landscapes of essential thrombocythaemia in adolescents and young adults.

Essential thrombocythaemia (ET) in adolescents and young adults (AYA, 15-39 years) is a distinct entity with an incompletely defined prognosis. In this multicentre retrospective study, 1728 ET patients from 29 centres across China were stratified into AYA (n = 328) and non-AYA (≥40 years, n = 1400) cohorts. We compared their clinical profiles, genomic landscapes, long-term outcomes and risk factors for progression to post-ET myelofibrosis (MF). AYA patients had fewer cardiovascular risks and lower thrombosis rates, but higher rates of extreme thrombocytosis. Molecularly, AYA patients were enriched for calreticulin (CALR) mutations, whereas Janus kinase 2 (JAK2) predominated in older patients. The burden of non-driver mutations (tet methylcytosine dioxygenase 2 [TET2], DNA methyltransferase 3A [DNMT3A], ASXL transcriptional regulator 1 [ASXL1], SH2‑B adaptor protein 3 [SH2B3]) was lower in AYA patients. Consequently, AYA patients achieved superior long-term outcomes across all key survival endpoints, including overall, myelofibrosis-free and leukaemia-free survival. Analysis of post-ET MF progression risks identified age-specific patterns: CALR mutations are enriched in younger patients and show an age-specific association with MF progression. AYA-ET constitutes a unique clinicomolecular subtype with a favourable prognosis, supporting age-stratified management. The enrichment of CALR mutations and their specific link to MF progression in young patients underscore the urgent need for targeted therapies against CALR-mutant clones.

adolescents and young adults (AYA)↗

PubMed2026

Clonal Hematopoiesis and Incident Heart Failure.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association. OBJECTIVE: To test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association. DESIGN, SETTING, AND PARTICIPANTS: This was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025. EXPOSURES: Presence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD). MAIN OUTCOMES AND MEASURES: The primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors. RESULTS: Among 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.

Adult↗

PubMed2026

Anti-inflammatory activity of an IL-6 missense variant against crystal-induced inflammatory response.

Interleukin-6 (IL-6) has an important modulator effect on inflammation and immunity and is involved in the progression of nephrolithiasis (kidney stone). However, whether IL-6 genetic variants affect the pathogenesis of kidney stones remains unclear. The present study conducted a combined investigation of candidate gene-driven screening and systematic screening on whole exome sequencing data from 28 patients of calcium oxalate stones, identifying a non-synonymous single nucleotide polymorphism (SNP) rs13306435 in IL-6 as a candidate research locus, which was further validated using HRM genotyping in an expanded cohort comprising 241 cases and 229 healthy subjects. Western blotting and qRT-PCR were used to assess the effects of this variant on crystal-induced inflammation, while molecular dynamics simulation was employed to analyze structural alterations in the receptor binding complex. In individuals aged ≤40 years, the A allele of rs13306435 was nominally associated with a reduced risk of stone formation, but no association was observed for the whole population. This missense variant causes an aspartate-to-glutamate substitution (D/E), inhibiting calcium oxalate monohydrate (COM)-triggered JAK2/STAT3 activation and inflammatory responses. However, it decreased the binding energy of IL-6/IL-6R/gp130 complex by increasing hydrogen bonds and salt brigdge at remote interfaces, suggesting that enhanced receptor binding does not necessarily translate to increased downstream signaling. Although this variant is not associated with general stone susceptibility, it exhibits notable anti-inflammatory activity by attenuating COM-induced JAK2/STAT3 activation and may influence the progression of stones through this pathway. These findings provide new insights into the role of anti-inflammatory mechanisms in nephrolithiasis.

Humans↗

PubMed2026

pKAKA: a protein language model for prioritizing kinase-disrupting variants in diseases.

Protein kinases are pivotal regulators of cellular signaling, and their genetic variations are frequently implicated in diseases. Although numerous kinase mutations have been identified as drivers of altered activity, with a few successfully targeted therapeutically, the functional impact of most variants remains uncharacterized. To bridge this gap, we curate a comprehensive dataset that contains 2553 experimentally validated kinase activity-related key alterations (KAKAs) from the literature. While many mutations outside canonical functional regions are known to affect kinase activity, systematic methods to predict their functional consequences are lacking. Consequently, we develop a computational method to predict potential KAKAs, leveraging transfer learning on the pre-trained protein language model ProtBert. Our model, termed pKAKA, achieves an impressive AUC score of 0.9593 and outperforms the AlphaMissense benchmark in comparative testing. Systematic analysis of kinase missense mutations underscores the critical role of KAKAs in pathogenesis, with highlights including JAK2 V617F in atherosclerotic cardiovascular disease, LRRK2 G2385R in Parkinson's disease, EGFR L858R in lung adenocarcinoma, and EGFR G598V in glioma. Overall, this study significantly advances our understanding of how mutations that influence kinase activity contribute to disease mechanisms.

Humans↗

PubMed2026

Integrated bioinformatics analysis reveals cross-talking hub genes and therapeutic agents between sepsis and acute myocardial infarction.

BACKGROUND: Sepsis and acute myocardial infarction (AMI) are two significant diseases that may share overlapping etiological mechanisms. This study aims to systematically identify core genes common to both conditions and to explore their potential as therapeutic targets and drug candidates through an integrative analysis of clinical data and bioinformatics. METHODS: The AMI dataset was obtained from the GEO database, and RNA sequencing data were collected from blood samples of patients with sepsis at our hospital. Common genes were identified using differential expression gene analysis (DEG) and weighted gene co-expression network analysis (WGCNA). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were performed. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the MCC/Degree algorithm. Diagnostic value was assessed via receiver operating characteristic curve analysis. Immune infiltration patterns, single-cell sequencing data, and molecular docking simulations were employed to evaluate immune relevance and identify potential therapeutic compounds. RESULTS: A total of 417 genes were identified between sepsis and AMI, with enrichment analysis revealing significant involvement in inflammatory responses. Three hub genes-JAK2, MYD88, and TIMP1-were selected for further investigation. ROC curves confirmed their strong diagnostic performance for both diseases. Immune infiltration analysis showed that these core genes were significantly correlated with the infiltration levels of various immune cell types. Molecular docking indicated that quercetin exhibited stable binding affinity with the proteins encoded by these genes. qPCR validation further confirmed the upregulation of these three genes, supporting the anti-inflammatory effects of quercetin as a potential targeted therapy. CONCLUSION: JAK2, MYD88, and TIMP1 were identified as shared core genes in sepsis and AMI. These genes not only serve as potential diagnostic biomarkers but also offer novel targets for developing common therapeutic strategies for both conditions. Furthermore, quercetin emerges as a promising candidate for targeted treatment.

Humans↗

PubMed2026

Clinical and genetic features of Ph-negative myeloproliferative neoplasms with dual-driver gene positivity.

OBJECTIVES: To investigate the clinical laboratory characteristics and gene mutation features of dual-driver gene positivity in patients with Philadelphia chromosome-negative myeloproliferative neoplasm (Ph-negative MPN). METHODS: We conducted a retrospective analysis of clinical data and genetic test results from 203 newly diagnosed patients with Ph-negative MPN. Of these, 194 had single-driver gene positivity and 9 had dual-driver gene positivity. High-throughput sequencing was used to detect mutations in JAK2, CALR, and MPL. Clinical characteristics and gene mutation profiles were compared between the two patient groups. RESULTS: The incidence of dual-driver gene positivity was 4.4% (9/203), with the most common combinations being JAK2 with CALR (4 patients) and JAK2 with MPL (4 patients). Compared with the single-driver group, the dual-driver group had a significantly higher risk of bleeding [4.1% (8/194) vs. 33.3% (3/9), P = 0.008] and a higher proportion of uncommon mutations [3.6% (7/194) vs. 33.3% (3/9), P = 0.006]. No statistically significant differences were observed between the two groups regarding age, thrombosis incidence, splenomegaly, or routine blood test indicators. During follow-up, 1 patient in the dual-driver group died from cerebrovascular disease. No leukaemia transformation or disease-related deaths occurred among the remaining patients. DISCUSSION: The increased bleeding risk in dual-driver patients may be related to a higher proportion of CALR mutations, elevated platelet counts, and higher variant allele frequencies, though these findings require validation in larger cohorts due to the small sample size. The higher prevalence of uncommon mutations suggests a more complex mutational landscape in this subgroup. CONCLUSION: Patients with Ph-negative MPN and dual-driver gene positivity may have a higher risk of bleeding and a more complex gene mutation profile.

Humans↗

PubMed2026

A distinct psoriasis-atopic dermatitis overlapping phenotype in adults with dual type 2 and type 3 immune features and favorable response to Janus kinase 1 inhibition.

BACKGROUND: Patients exhibiting overlapping histopathologic features of psoriasis (Pso) and atopic dermatitis (AD) present a diagnostic and therapeutic challenge. OBJECTIVES: To delineate the clinicopathological and immunologic portrait of psoriasis-atopic dermatitis overlapping (Pso-Ec) for integrated diagnosis and therapeutic decision-making. METHODS: We conducted a 2-center prospective study comparing 30 Pso-Ec patients with typical Pso and AD cohorts. Clinicopathological characteristics and immunologic profiling of lesional skin and peripheral blood were analyzed, and treatment courses were assessed. RESULTS: Pso-Ec patients (aged 13-72 years; mean age: 49.7 years) presented with ill-defined erythematous plaques with thin scales, excoriation, intense itching, and mixed psoriatic-eczematous histology. Immune profiling showed co-existence of helper T cell 2/cytotoxic T cell 2 and helper T cell 17/cytotoxic T cell 17 in skin and blood, with Janus kinase (JAK) 1 signal transducer and activator of transcription 2/6 signaling involvement. Responses to prior Pso-targeted (n = 18) and AD-targeted (n = 15) biologics were often inadequate. In contrast, JAK1 inhibitors achieved minimal disease activity (body surface area ≤ 2, numerical rating scale ≤1) during a median follow-up of 17 months. No progression to classic Pso or AD phenotypes was observed. LIMITATIONS: Sample size was limited and immunologic analyses were performed in a representative subset of patients. CONCLUSIONS: Pso-Ec represents a distinct, predominantly adult-onset phenotype driven by dual type 2 and type 3 inflammation, and JAK1 inhibitors appear as an effective option.

Humans↗

PubMed2025

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus. RESULTS: We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib. CONCLUSION: Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

Humans↗

PubMed2026

Shared genetic architecture and therapeutic targets across paediatric immune-mediated diseases.

OBJECTIVES: Paediatric-onset immune-mediated inflammatory diseases (IMIDs), including juvenile idiopathic arthritis and related rheumatic diseases, remain genetically undercharacterised. We aimed to define shared and category-specific genetic architecture across paediatric IMIDs, compare signals with adult IMIDs, and identify therapeutic opportunities. METHODS: We analysed 24 paediatric IMIDs classified as autoimmune, polygenic-autoinflammatory, mixed-pattern, or allergic. Genome-wide association analyses included 18,086 cases and 131,019 controls of European ancestry. We estimated single nucleotide polymorphism (SNP)-based heritability, genetic correlations, and polygenic overlap; performed subset-based meta-analysis; and conducted functional annotation, gene prioritisation, pathway and protein network analyses, adult-IMID comparison, and drug-target prioritisation. RESULTS: SNP-based heritability ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs. Genetic correlation and polygenic modelling supported partial sharing across categories with category-specific components. Meta-analysis identified 39 genome-wide significant loci outside the Major Histocompatibility Complex (MHC) region, including 15 previously unreported loci; 19 loci were shared between categories. Gene-prioritisation and protein interaction analyses identified a core MHC-centred antigen-presentation network, with category-enriched modules involving complement, innate/barrier pathways, epithelial biology, and type 2 immunity. Enriched pathways included nuclear factor κB signalling, T helper 17 related pathways, Janus kinase-signal transducer and activator of transcription signalling, programmed cell death protein 1/programmed death‑ligand 1, cytotoxic T‑lymphocyte associated protein 4 regulation, and osteoclast differentiation, several of which are relevant to rheumatic diseases. Paediatric IMIDs shared broad polygenic architecture with adult IMIDs, whereas top-ranked genes converged strongly with adult rheumatic diseases. Priority Index analysis identified 178 high-scoring genes, including 43 approved or investigational IMID drug targets. CONCLUSIONS: Paediatric-onset IMIDs share core pathways with adult forms but exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These findings provide a genomic framework for paediatric precision medicine, guiding classification, risk prediction, and therapeutic development.

Humans↗

PubMed2026

Targeting pancreatic cancer progression: The formononetin and salvianolic acid B combination suppresses JAK/STAT signaling via MBOAT2 downregulation.

OBJECTIVE: Formononetin and salvianolic acid B (FcS) are the primary bioactive components of the Astragalus mongholicus-Salvia miltiorrhiza herbal pair, a classic combination for treating pancreatic cancer associated with qi deficiency and blood stasis. This study elucidates the therapeutic potential and mechanisms of FcS in the treatment of pancreatic cancer. METHODS: A zebrafish xenograft model was used to screen bioactive combinations derived from A. mongholicus and S. miltiorrhiza, identifying FcS as a candidate with antitumor activity. Its efficacy was evaluated in vivo using the zebrafish model, orthotopic LSL-KrasG12D/+, LSL-Trp53R172H/+ and Pdx-1-Cre (KPC) mice, and subcutaneous xenograft models. Cell viability and proliferation were assessed using cell counting kit-8, 5-ethynyl-2'-deoxyuridine and colony formation assays, and migration and invasion were evaluated by wound healing and transwell assays. Membrane-bound O-acyltransferase 2 (MBOAT2) was identified as a potential target through a molecular docking study and the Cancer Genome Atlas (TCGA) analysis. MBOAT2 knockdown cells were used to explore its roles and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in FcS-mediated inhibition. RESULTS: In the zebrafish model, FcS strongly inhibited pancreatic tumor growth. FcS reduced tumor volume, the expression of proliferation marker Ki-67, and proliferating cell nuclear antigen in KPC mice. In vitro, FcS inhibited pancreatic cancer cell viability, proliferation, migration and invasion, which was accompanied by downregulation of MBOAT2 expression. TCGA analysis linked high MBOAT2 expression to aggressive phenotypes. MBOAT2 knockdown reduced the survival, proliferation and invasion of BxPC-3 cells. Rescue experiments revealed that MBOAT2 knockdown attenuated the antitumor effects of FcS, possibly through modulation of the JAK/STAT signaling pathway. FcS also inhibited tumor proliferation in xenograft models, and MBOAT2 expression was elevated in tumor tissues from pancreatic cancer patients. CONCLUSION: FcS suppresses pancreatic cancer progression via MBOAT2 downregulation and JAK/STAT pathway inhibition, which highlights MBOAT2 as a potential therapeutic target. Please cite this article as: Xu Y, Xu CS, Jin HB, Gu WG, Shen HZ, Lu L, Chen Y, Xu DC, Zhang XF, Yang JF, Wang Y. Targeting pancreatic cancer progression: The formononetin and salvianolic acid B combination suppresses JAK/STAT signaling via MBOAT2 downregulation. J Integr Med. 2026; 24(5):725-741.

Animals↗

PubMed2025

Comparative Efficacy of Janus Kinase Inhibitors Indicated for Severe Alopecia Areata: A Bayesian Network Meta-Analysis and Matching-Adjusted Indirect Comparison.

Systemic Janus kinase inhibitors (JAKIs) have markedly advanced the therapeutic landscape for alopecia areata (AA). Although baricitinib and ritlecitinib are approved in the United States (US) and Europe, and deuruxolitinib in the US for severe AA, the lack of head-to-head randomized controlled trials (RCTs) limits evidence-based prescribing decisions. Moreover, prior meta-analyses excluded data on certain oral JAKIs or incorporated findings from agents and dosing regimens that were abandoned, investigational, clinically ineffective, or associated with unacceptable safety profiles. To compare the efficacy of oral JAKIs, limited to FDA, EMA, or MHRA approved drugs and doses-baricitinib (2 and 4 mg QD), ritlecitinib (50 mg QD), and deuruxolitinib (8 mg BID)-for severe AA, using advanced indirect comparison methodologies. A systematic review was performed following PRISMA 2020 guidelines (CRD420251116775). Bayesian network meta-analysis (NMA) synthesized data from RCTs reporting Week 24 outcomes on Severity of Alopecia Tool (SALT) ≤ 10 and SALT ≤ 20 thresholds. Multilevel network meta-regression (ML-NMR) evaluated heterogeneity and adjusted for baseline imbalances. Additionally, unanchored matching-adjusted indirect comparisons (MAIC) were conducted using individual patient-level data from THRIVE trials. Surface under the cumulative ranking (SUCRA) values were calculated to rank treatments. Seven RCTs (n = 4560 participants) were included. Deuruxolitinib 8 mg significantly outperformed baricitinib 2 and 4 mg on both SALT endpoints. Differences with ritlecitinib 50 mg were directionally favorable for deuruxolitinib but not statistically significant in NMA and ML-NMR models. MAICs confirmed superior odds for deuruxolitinib versus baricitinib 2 mg (OR = 71.55) and ritlecitinib (OR = 18.27) for SALT ≤ 20. SUCRA rankings also consistently favored deuruxolitinib. Among approved oral JAKIs, deuruxolitinib 8 mg shows the highest short-term efficacy for severe AA. These findings provide preliminary evidence to guide treatment decisions but should be interpreted as exploratory pending confirmation.

Humans↗

PubMed2026

The tumor suppressor NDRG2 recruits protein phosphatase 2A to suppress STAT5 phosphorylation in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy with a poor prognosis that is caused by human T-cell leukemia virus type 1 infection. We previously demonstrated that N-myc downstream-regulated gene 2 (NDRG2) is significantly downregulated in ATL, resulting in aberrant activation of the signal transduction pathways through the dissociation of serine/threonine protein phosphatase 2A. To identify potential targets of NDRG2, we performed comprehensive mass spectrometry of differentially phosphorylated peptides in ATL cells with overexpression of NDRG2 using a TiO2-based enrichment method. Kyoto Encyclopedia of Genes and Genomes and gene ontology analysis revealed that the downregulated phosphopeptides correlated with signaling pathways, T-cell differentiation, and proliferation. Our results identified signal transducer and activator of transcription 5B as a novel NDRG2-regulated protein that is dephosphorylated at serine 193 and tyrosine 699. Although enforced expression of NDRG2 in ATL cell lines does not change the phosphorylation of Janus kinase 3, an upstream regulator of STAT5, phosphorylated STAT5 at tyrosine and serine is significantly suppressed by the direct binding to STAT5 with NDRG2 leading to the inhibition of STAT5 downstream gene expression. Furthermore, NDRG2 binds to STAT5B with alanine replacement of Y699 (Y699A), but only weakly associates with S193A, suggesting that NDRG2 is directly involved in serine phosphorylation through the recruitment of serine/threonine protein phosphatase 2A to STAT5. Because S193 A remarkably induces reduced phosphorylation of Y699 and subsequent transcriptional activity, the induction of serine phosphorylation through the loss of NDRG2 expression is dispensable for STAT5 tyrosine phosphorylation and activity. Since the loss of NDRG2 expression is essential factor to maintenance of ATL cells by STAT5 activity through phosphorylation of serine and tyrosine, targeting STAT5 becomes a feasible and effective strategy in NDRG2-deficient ATL.

Humans↗