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    BIOMARKER:

    STAT3 mutation

    i
    Other names: STAT3, Signal Transducer And Activator Of Transcription 3, Acute-Phase Response Factor , APRF, Signal Transducer And Activator Of Transcription 3 (Acute-Phase Response Factor), DNA-Binding Protein APRF, ADMIO1, ADMIO, HIES
    Entrez ID:
    6774
    Related biomarkers:
    Expression
    Mutation
    Others
    10d
    Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis. (PubMed, Front Immunol)
    STAT3 activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, STAT3 activating mutations may play a role in disease pathogenesis in a subset of RA patients.
    Journal
    |
    CD8 (cluster of differentiation 8) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation • STAT3 D661Y • STAT3 Y640F
    25d
    A Case of Plasmablastic Lymphoma Complicated with Pure Red Cell Aplasia Caused by T-cell Large Granular Lymphocytic Leukemia. (PubMed, Intern Med)
    Large granular lymphocytes and T-cell receptor rearrangement were detected, thus leading to the diagnosis of T-LGLL and PRCA. This is the first documented case of PBL with T-LGLL and PRCA, offering insight into PBL's pathophysiology and the complications of PBL.
    Journal • IO biomarker
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    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    26d
    Systemic ALK-Negative Anaplastic Large Cell Lymphoma: Insights into Morphologic, Immunophenotypic, Genetic and Molecular Characteristics. (PubMed, Hum Pathol)
    Gene expression profiling data have shownthat ALK-negative ALCL has distinctive molecular signatures, different from ALK+ ALCL and other T-cell lymphomas. Better understanding of the morphologic, immunophenotypic, genetic and molecular features of ALK-negative ALCL will help establish the correct diagnosis, guide therapeutic strategies and improve patient outcomes.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • JAK2 (Janus kinase 2) • TNFRSF8 (TNF Receptor Superfamily Member 8) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • JAK1 (Janus Kinase 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • TYK2 (Tyrosine Kinase 2) • TP63 (Tumor protein 63) • DUSP22 (Dual Specificity Phosphatase 22) • USP22 (Ubiquitin Specific Peptidase 22)
    |
    ALK positive • ALK rearrangement • TNFRSF8 expression • ALK negative • STAT3 mutation • JAK1 mutation
    6ms
    Integrated Clinical Genotype-phenotype Characteristics of STAT3-mutated Myeloid Neoplasms. (PubMed, Clin Cancer Res)
    STAT3 mutation is present in various MNs, but not in MPN. It is often an early event or occurs upon leukemic transformation, suggesting an important role in the pathogenesis and progression of MNs by activating JAK-STAT pathway. It may help identify a subset of patients with MNs who may benefit from targeted therapy.
    Journal
    |
    ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • SETBP1 (SET Binding Protein 1)
    |
    ASXL1 mutation • TET2 mutation • SRSF2 mutation • STAT3 mutation • STAT3 Y640F
    6ms
    PRMT5-mediated methylation of STAT3 is required for lung cancer stem cell maintenance and tumour growth. (PubMed, Commun Biol)
    Indeed, NSCLC cells expressing the STAT3 mutant which R609 was replaced to alanine (R609K) show significantly impaired tumour growth in nude mice. Overall, our study reveals a mechanism by which STAT3 remains activated in NSCLC and provides a new target for cancer therapeutic approaches.
    Journal • Cancer stem
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    STAT3 (Signal Transducer And Activator Of Transcription 3) • PRMT5 (Protein Arginine Methyltransferase 5)
    |
    STAT3 mutation • STAT3 expression
    6ms
    Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study. (PubMed, Signal Transduct Target Ther)
    Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.
    P1/2 data • Clinical Trial,Phase I • Clinical Trial,Phase II • Journal • PD(L)-1 Biomarker • IO biomarker • Epigenetic controller
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    |
    Tyvyt (sintilimab) • Epidaza (chidamide)
    7ms
    Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment. (PubMed, Cancers (Basel))
    The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.
    Review • Journal
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation • FASN-L • STAT5A mutation
    7ms
    Targeting PARG induces tumor cell growth inhibition and antitumor immune response by reducing phosphorylated STAT3 in ovarian cancer. (PubMed, J Immunother Cancer)
    We have identified a novel antitumor mechanism underlying PARG inhibition beyond its primary antitumor effects through blocking DDR in ovarian cancer. Furthermore, targeting PARG activates antitumor immune responses, thereby potentially increasing response rates to immunotherapy in patients with ovarian cancer.
    Journal • BRCA Biomarker • IO biomarker • Tumor cell
    |
    BRCA1 (Breast cancer 1, early onset)
    |
    STAT3 mutation
    8ms
    Fucoxanthin induces human melanoma cytotoxicity by thwarting the JAK2/STAT3/BCL-xL signaling axis. (PubMed, Environ Toxicol)
    Mechanistically, Fucoxanthin targets the JAK2/STAT3/BCL-xL antiapoptotic axis to provoke melanoma cell death. This discovery implicates the potential application of Fucoxanthin as a chemopreventive or therapeutic strategy for melanoma management.
    Journal
    |
    JAK2 (Janus kinase 2) • IL6 (Interleukin 6) • BCL2L1 (BCL2-like 1)
    |
    STAT3 mutation
    9ms
    Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3. (PubMed, Mol Ther Nucleic Acids)
    To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC)...Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.
    Journal • IO biomarker
    |
    BCL2L1 (BCL2-like 1) • CRBN (Cereblon) • STAT3 (Signal Transducer And Activator Of Transcription 3) • TLR9 (Toll Like Receptor 9) • CCND2 (Cyclin D2) • STAT1 (Signal Transducer And Activator Of Transcription 1) • STAT5A (Signal Transducer And Activator Of Transcription 5A)
    |
    STAT3 mutation • BRAF K601
    |
    thalidomide
    9ms
    Mutational Landscape and Clinicopathologic Features of Plasmablastic Lymphoma (USCAP 2024)
    In conclusion, our findings shed light on the unique molecular complexity of PBL, unveiling its mutational landscape and potential therapeutic targets. Due to the rarity of PBL, further research with a more extensive sample size is essential to completely elucidate the mutational landscape of PBL.
    Clinical
    |
    KRAS (KRAS proto-oncogene GTPase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • TNFRSF8 (TNF Receptor Superfamily Member 8) • STAT3 (Signal Transducer And Activator Of Transcription 3) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • SDC1 (Syndecan 1) • TCF3 (Transcription Factor 3) • CCND3 (Cyclin D3) • CD79A (CD79a Molecule) • TNFRSF13B (TNF Receptor Superfamily Member 13B)
    |
    KRAS mutation • KRAS G12V • MYD88 mutation • KRAS G12 • KRAS G13 • PDGFRA mutation • STAT3 mutation
    |
    Archer® FusionPlex® Lymphoma
    9ms
    Targeting C21orf58 is a Novel Treatment Strategy of Hepatocellular Carcinoma by Disrupting the Formation of JAK2/C21orf58/STAT3 Complex. (PubMed, Adv Sci (Weinh))
    It is demonstrated that C21orf58 displays an oncogenic role in promoting cell growth, tumorigenesis and sorafenib resistance of HCC cells by abnormal activation of STAT3 signaling...Moreover, it is validated that inhibition of C21orf58 with drug alminoprofen, selected by virtual screening, could effectively repress the viability and tumorigenesis of HCC cells. Therefore, it is identified that C21orf58 functions as an oncogenic adaptor, reveal a novel regulatory mechanism of JAK2/STAT3 signaling, explain the cause of abnormal activity of activated mutants of STAT3, and explore the attractive therapeutic potential by targeting C21orf58 in HCC.
    Journal
    |
    JAK2 (Janus kinase 2) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    |
    sorafenib
    10ms
    CXCL12-CXCR4 mediates CD57 CD8 T cell responses in the progression of type 1 diabetes. (PubMed, J Autoimmun)
    Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57 CD8 T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57 CD8 T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.
    Journal
    |
    CD8 (cluster of differentiation 8) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CXCL12 (C-X-C Motif Chemokine Ligand 12) • B3GAT1 (Beta-1,3-Glucuronyltransferase 1)
    |
    STAT3 mutation
    |
    LY2510924
    10ms
    The constitutive activation of STAT3 gene and its mutations are at the crossroad between LGL leukemia and autoimmune disorders. (PubMed, Blood Cancer J)
    Overall, this review sheds light on the intricate relationships between inflammation and cancer, emphasizing the importance of the STAT3 gene and its activation in the pathophysiology of these conditions. Gaining a deeper understanding of these underlying mechanisms seeks to pave the way for the development of novel targeted therapies for patients affected by inflammation-related cancers.
    Review • Journal
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    10ms
    Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets. (PubMed, Anticancer Res)
    Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    TP53 (Tumor protein P53)
    |
    PD-L1 expression • TP53 mutation • STAT3 mutation • TP53 expression
    |
    GLG-302
    11ms
    Clinicopathological and genetic landscape of plasmablastic lymphoma in Taiwan. (PubMed, Pathol Res Pract)
    Deletion of chromosome 13q14 was frequent. The PBL cases in Taiwan showed recurrent mutations involving JAK-STAT, RAS-MAPK, epigenetic regulation, and NOTCH signaling pathways, findings similar to that from the West.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • CD20 (Membrane Spanning 4-Domains A1) • CCND1 (Cyclin D1) • BCL6 (B-cell CLL/lymphoma 6) • STAT3 (Signal Transducer And Activator Of Transcription 3) • SDC1 (Syndecan 1) • CD79A (CD79a Molecule) • IRF4 (Interferon regulatory factor 4)
    |
    KRAS mutation • NRAS mutation • MYC expression • MYC rearrangement • FGFR3 fusion • STAT3 mutation • Chr del(13)(q14)
    11ms
    Upregulation of tumor suppressor PIAS3 by Honokiol promotes tumor cell apoptosis via selective inhibition of STAT3 tyrosine 705 phosphorylation. (PubMed, J Nat Med)
    Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.
    Journal • Tumor cell
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3) • PIAS4 (Protein Inhibitor Of Activated STAT 4)
    |
    STAT3 mutation
    11ms
    Signaling Pathway Alterations Driven by BRCA1 and BRCA2 Germline Mutations are Sufficient to Initiate Breast Tumorigenesis by the PIK3CAH1047R Oncogene. (PubMed, Cancer Res Commun)
    Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation.  .
    Journal • BRCA Biomarker
    |
    PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • TERT (Telomerase Reverse Transcriptase) • IL6 (Interleukin 6) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • STAT3 (Signal Transducer And Activator Of Transcription 3) • EPAS1 (Endothelial PAS domain protein 1) • BRD4 (Bromodomain Containing 4) • FOXO3 (Forkhead box O3) • PDK1 (Pyruvate Dehydrogenase Kinase 1) • TNFSF11 (TNF Superfamily Member 11)
    |
    BRCA2 mutation • BRCA1 mutation • PIK3CA mutation • PIK3CA H1047R • BRCA1 mutation + BRCA2 mutation • STAT3 mutation
    12ms
    T-Cell Lgll of the Γδ Subtype: Clinically Relevant Fact or Academically Interesting Finding? (ASH 2023)
    First line single agent therapy with methotrexate (MTX), cyclosporine, and cyclophosphamide have shown similar overall response rates of 40-50%, though STAT3 mutated disease is associated with better response to MTX...Our patient was initiated on prednisone, though due to poor tolerance was transitioned to MTX titrated to 12...The same study found better responses to cyclosporine as first line therapy, an interesting observation as MTX has been generally accepted as first line therapy based on predominantly retrospective studies, though these studies did not stratify treatment responses by TCR phenotype. These findings underscore the need for prospective studies characterizing Tγδ specific disease course, survival analyses and treatment response.
    Clinical
    |
    CD8 (cluster of differentiation 8) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CD4 (CD4 Molecule) • NCAM1 (Neural cell adhesion molecule 1) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • CD7 (CD7 Molecule) • CD2 (CD2 Molecule) • B3GAT1 (Beta-1,3-Glucuronyltransferase 1)
    |
    ASXL1 mutation • TET2 mutation • STAT3 mutation • STAT3 D661Y • STAT3 Y640F
    |
    cyclophosphamide • methotrexate • prednisone • cyclosporine
    12ms
    The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis. (PubMed, Cell Signal)
    In comparisons with the inoculation of STAT3-KD cells reconstituted with wild-type STAT3, the inoculation of STAT3-KD cells reconstituted with the K685R mutant significantly enhanced tumorigenesis and hepatosplenomegaly in nude mice. Collectively, these results revealed for the first time that the acetylation of STAT3 at K685 attenuated NPM-ALK-induced oncogenesis.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1) • IL6 (Interleukin 6) • STAT3 (Signal Transducer And Activator Of Transcription 3) • TCF3 (Transcription Factor 3) • PIM1 (Pim-1 Proto-Oncogene) • SOCS3 (Suppressor Of Cytokine Signaling 3)
    |
    ALK translocation • STAT3 mutation • STAT3 expression
    1year
    A systematic review regarding the prevalence of malignancy in patients with the hyper-IgE syndrome. (PubMed, Clin Exp Med)
    The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.
    Review • Journal
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3) • TYK2 (Tyrosine Kinase 2) • DOCK8 (Dedicator Of Cytokinesis 8)
    |
    STAT3 mutation • DOCK8 mutation
    1year
    Insights into Large Granular Lymphocytic Leukemia-Associated Hemolytic Anemia: Clinical Associations, Therapeutic Responses, and Optimal Management Strategies from a Large Institutional Study (ASH 2023)
    Other first-line treatments and their corresponding median duration of response (months) included cyclosporine (n=7, 72 months), cyclophosphamide (n=5, 72 months), IVIG (n=1, 16 months), and methotrexate (n=11, 21 months). Subsequent lines of therapy included campath (n=9), cyclosporine (CSA) (n=4), cyclophosphamide (n=9), intravenous immunoglobulin (IVIG) (n=2), MTX (n=4), rituximab (n=1), sirolimus (n=1), tacrolimus (n=2), and tofacitinib (n=2)...These significant findings contribute substantially to advancing our comprehension of LGLL-associated HA and its optimal management strategies. AIHA in patients with LGLL points towards a global immune dysfunction in this disease beyond clonal cytotoxic T/NK cell expansion.
    Clinical
    |
    CD8 (cluster of differentiation 8)
    |
    STAT3 mutation
    |
    Rituxan (rituximab) • cyclophosphamide • methotrexate • Campath (alemtuzumab) • sirolimus • cyclosporine • tofacitinib
    1year
    Pathogenetic Subtypes of Pure Red Cell Aplasia and Therapeutic Management Strategies : A Single Centre Experience in the United Kingdom of 75 Patients over 10 Years (ASH 2023)
    Most common second line therapy was Ciclosporin (22.3%) followed by Cyclophosphamide (4%), Sirolimus (2.7%) and Anti-Thymocyte Globulin (1.33%)...Other therapies received were IVIG, erythropoietin and disease-directed therapy,e.g lenalidomide for MDS with 5q- and thymectomy...Response to initial therapy was seen in the majority of idiopathic PRCA patients, however response was lower in patients with an underlying malignancy. Of note we identified STAT3 mutations in two patients, highlighting the role of molecular testing and keeping a broad differential diagnosis when presented with this rare condition.
    Clinical
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    |
    lenalidomide • cyclophosphamide • sirolimus • cyclosporine
    1year
    Clinical Features and Outcomes in Large Granular Lymphocyte Leukemia-Associated Pure Red Cell Aplasia with STAT3 Mutation (ASH 2023)
    The initial dose of cyclophosphamide and prednisone were 100mg/day and 0.5-1mg/kg/day, respectively...The complete response rate (CRR) [31% (5/16) vs 33% (19/58), P=0.909] and overall response rate (ORR) [56% (9/16) vs 50% (29/58), P=0.658] of cyclosporine (CsA) treatment were similar in patients with STAT3 mutations or not...Leukemia. 2020, 34: 1116–1124.
    Clinical • IO biomarker
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation • STAT3 Y640F
    |
    cyclophosphamide • prednisone • cyclosporine
    1year
    Ruxolitinib Promotes Clinical Responses in Large Granular Lymphocytic Leukemia Via Suppression of JAK/STAT-Dependent Inflammatory Cascades (ASH 2023)
    Commonly used agents include low doses of methotrexate or cyclophosphamide. Ruxolitinib induced durable responses in pts with LGL and therefore may represent an option for pts requiring treatment. STAT3 mutation status was predictive of EFS and responses were associated with JAK/STAT pathway down-regulation, demonstrating on-target effects. Integrated immune profiling suggests that ruxolitinib may interrupt JAK/STAT-dependent paracrine inflammatory signals that promote bone marrow suppression.
    Clinical • PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • JAK2 (Janus kinase 2) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • JAK1 (Janus Kinase 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • GZMB (Granzyme B) • PRF1 (Perforin 1) • NKG7 (Natural Killer Cell Granule Protein 7)
    |
    JAK2 mutation • STAT3 mutation • JAK1 mutation
    |
    Jakafi (ruxolitinib) • cyclophosphamide • methotrexate
    1year
    Ruxolitinib for the Treatment of T-Cell Large Granular Lymphocytic Leukemia (clinicaltrials.gov)
    P2, N=28, Recruiting, John Reneau | Not yet recruiting --> Recruiting
    Enrollment open
    |
    CD8 (cluster of differentiation 8) • STAT3 (Signal Transducer And Activator Of Transcription 3) • B3GAT1 (Beta-1,3-Glucuronyltransferase 1)
    |
    STAT3 mutation
    |
    Jakafi (ruxolitinib)
    1year
    Methoxyhispolon Methyl Ether, a Hispolon Analog, Thwarts the SRC/STAT3/BCL-2 Axis to Provoke Human Triple-Negative Breast Cancer Cell Apoptosis In Vitro. (PubMed, Biomedicines)
    Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent.
    Preclinical • Journal • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • IL6 (Interleukin 6) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    BCL2 overexpression • STAT3 mutation
    1year
    Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether. (PubMed, Biomedicines)
    5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate...We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/β-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.
    Preclinical • Journal • IO biomarker
    |
    BCL2 (B-cell CLL/lymphoma 2) • IL6 (Interleukin 6) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    |
    5-fluorouracil
    1year
    A Pilot Study of Siltuximab in Large Granular Lymphocytic Leukemia (LGLL) – Trial in Progress (SOHO 2023)
    Current treatment using immunosuppressive doses of methotrexate, cyclophosphamide, or cyclosporine A has modest efficacy, and the responses are usually not durable. No new safety signal was observed. The study is actively recruiting at Moffitt Cancer Center, Tampa, FL.
    Clinical
    |
    IL6 (Interleukin 6)
    |
    STAT3 mutation
    |
    cyclophosphamide • methotrexate • Sylvant (siltuximab)
    1year
    Genomic landscape of T-large granular lymphocyte leukemia and chronic lymphoproliferative disorder of NK cells: a single institution experience. (PubMed, Leuk Lymphoma)
    Additionally, TET2-only mutated T-LGLL (n = 5) had a significant reduction in platelet values compared with the WT (n = 16) or STAT3-only mutated T-LGLL (n = 12) (p < 0.05). In conclusion, we compared the somatic mutational landscape between STAT3/STAT5B WT and mutated patients and correlate with their distinct clinical characteristics.
    Journal
    |
    TET2 (Tet Methylcytosine Dioxygenase 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
    |
    TET2 mutation • STAT3 mutation
    over1year
    Sertindole, an Antipsychotic Drug, Curbs the STAT3/BCL-xL Axis to Elicit Human Bladder Cancer Cell Apoptosis In Vitro. (PubMed, Int J Mol Sci)
    Overall, the current study indicated sertindole exerts bladder cancer cytotoxicity by provoking apoptosis through targeted inhibition of the antiapoptotic STAT3/BCL-xL signaling axis. These findings implicate the potential to repurpose sertindole as a therapeutic strategy for bladder cancer.
    Preclinical • Journal
    |
    BCL2L1 (BCL2-like 1) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    over1year
    Prevalence of STAT3 mutations in patients with rheumatoid arthritis-associated T-cell large granular lymphocytic leukaemia and Felty syndrome. (PubMed, Clin Exp Rheumatol)
    The results suggest that STAT3 mutations are significantly less common in FS than in RA-associated T-LGL leukaemia. Moreover, NGS can detect clones undetectable by fragment analysis. We speculate that in patients with RA and neutropenia, the detection of STAT3 mutations can point to T-LGL leukaemia even in the absence of clonal TCR rearrangement.
    Journal • IO biomarker
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    over1year
    Context-dependent T-cell Receptor Gene Repertoire Profiles in Proliferations of T Large Granular Lymphocytes. (PubMed, Hemasphere)
    Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations that cause symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL lymphoproliferations on the other. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon when co-occurring with other malignancies, possibly reactive toward tumor antigens.
    Journal • IO biomarker
    |
    STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    STAT3 mutation
    over1year
    Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia. (PubMed, Haematologica)
    Moreover, T-LGLL patients' monocytes showed abnormal activation of signaling pathways, further supporting the different pathogenetic role of monocytes in patients with discrete clinical settings. Altogether, our data contribute to deepen the knowledge on the different cell subtypes in TLGLL, particularly focusing on non-leukemic cell populations and thus offering the rationale for new therapeutic strategies.
    Journal • Inflammatory cell
    |
    CD8 (cluster of differentiation 8) • IL6 (Interleukin 6) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CD4 (CD4 Molecule) • STAT5B (Signal Transducer And Activator Of Transcription 5B)
    |
    STAT3 mutation
    over1year
    Establishment and characterization of a novel breast implant-associated anaplastic large cell lymphoma cell line and PDX model (BIA-XR1) with a unique KRAS mutation. (PubMed, Curr Res Transl Med)
    Next-generation sequencing revealed a STAT3 mutation, commonly detected in BIA-ALCL, and a unique KRAS mutation reported for the first time in this lymphoma type. Both JAK/STAT3 and RAS/MEK/ERK oncogenic pathways were activated in BIA-XR1, which are targetable with clinically available agents.
    Preclinical • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • STAT3 (Signal Transducer And Activator Of Transcription 3)
    |
    KRAS mutation • STAT3 mutation
    over1year
    New Insights Into the Pathogenesis of T-Cell Lymphoma and How This May Guide Treatment (SOHO 2023)
    TFHLs, which frequently carry mutations of TET2, DNMT3A, RHOA and IDH2, rarely seen in combination in other PTCL, have a higher response rate to hypomethylating agents such as 5-azacytidine and histone deacetylase inhibitors such as romidepsin. Tumors harboring SVs or amplification of CD274 may show greater sensitivity to immune checkpoint inhibitors. Four tumor microenvironment subgroups defined by expression profiling alone, may represent immunotherapy biomarkers.
    PD(L)-1 Biomarker • IO biomarker
    |
    PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • RB1 (RB Transcriptional Corepressor 1) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • TET2 (Tet Methylcytosine Dioxygenase 2) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • JAK1 (Janus Kinase 1) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • CD4 (CD4 Molecule) • JAK3 (Janus Kinase 3) • RHOA (Ras homolog family member A) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • TBX21 (T-Box Transcription Factor 21) • TYK2 (Tyrosine Kinase 2) • DUSP22 (Dual Specificity Phosphatase 22) • GATA3 (GATA binding protein 3) • USP22 (Ubiquitin Specific Peptidase 22)
    |
    PD-L1 expression • TP53 mutation • ALK positive • DNMT3A mutation • ALK fusion • NOTCH1 mutation • CDKN2A deletion • TET2 mutation • CDKN2A mutation • RB1 deletion • PD-L1 amplification • ALK negative • STAT3 mutation
    |
    azacitidine • Istodax (romidepsin)
    over1year
    Analysis and Therapeutic Targeting of the IL-1R Pathway in Anaplastic Large Cell Lymphoma. (PubMed, Blood)
    Finally, the JAK2/IRAK1 dual inhibitor Pacritinib exhibited strong activities against pC ALK- ALCL where the IL-1R pathway is hyper-activated in the cell line and xenograft mouse model. Thus, our studies revealed critical insights into the essential roles of the IL-1R pathway in pC ALCL, and provided opportunities for developing novel therapeutic strategies.
    Journal
    |
    ALK (Anaplastic lymphoma kinase) • JAK2 (Janus kinase 2) • TNFRSF8 (TNF Receptor Superfamily Member 8) • IL1A (Interleukin 1, alpha) • IL1R1 (Interleukin 1 receptor, type I) • IRAK1 (Interleukin 1 Receptor Associated Kinase 1)
    |
    TNFRSF8 expression • ALK translocation • STAT3 mutation
    |
    Vonjo (pacritinib)
    over1year
    Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma. (PubMed, MedComm (2020))
    Moreover, WB737 inhibited STAT3 more potently than Stattic, resulting in a significant antitumor effect with undetectable toxicity, followed by almost complete tumor regression in an NKTL xenograft model harboring a STAT3-activating mutation. Taken together, these findings provide preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3-activating mutations.
    Preclinical • Journal
    |
    MYC (V-myc avian myelocytomatosis viral oncogene homolog) • STAT1 (Signal Transducer And Activator Of Transcription 1) • STAT2 (Signal transducer and activator of transcription 2)
    |
    MYC expression • STAT3 mutation