News - JAK3 mutation - LARVOL VERI

Pharmacological effects of koumine on acute lung injury in septic mice: From in vivo experiments and network pharmacology studies. (PubMed, Biochem Biophys Res Commun)

Network pharmacology analysis showed that 52 putative targets were relevant, and SLC6A4, HTR3A, JAK2 and JAK3 were the key targets. GO and KEGG pathway enrichment analysis showed that the related mechanisms involved neuroactive ligand-receptor interaction, calcium signaling pathway, serotonergic synapses, cholinergic synapses, etc. In summary, this study confirmed the potential therapeutic effect of koumine in sepsis induced ALI, suggesting its development prospect as a novel candidate drug for ALI, and providing data support.

1 month ago

Preclinical • Journal

JAK2 (Janus kinase 2) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • JAK3 (Janus Kinase 3) • IL1B (Interleukin 1, beta) • MPO (Myeloperoxidase) • SLC6A4 (Solute Carrier Family 6 Member 4)

JAK3 mutation

The Innate Immune System Surveillance Biomarker p87 in African Americans and Caucasians with Small High-Grade Dysplastic Adenoma [SHiGDA] and Right-Sided JAK3 Colon Mutations May Explain the Presence of Multiple Cancers Revealing an Important Minority of Patients with JAK3 Mutations and Colorectal Neoplasia. (PubMed, Gastrointest Disord (Basel))

Thus, this pilot study suggests that the reduction in p87 in the right colon is possibly correlated with JAK3 mutations. If confirmed, JAK3 mutations, known to be associated with immune aberrations, may provide a mechanistic explanation for the lack of a p87 (protein 87 kilodaltons) field in some patients with HGD polyps who might benefit from possible intervention such as more intensive screening. Limited microbiome studies were also performed on two patients with familial cancer syndromes and these compared favorably with controls available from the literature.

1 month ago

Journal

JAK3 (Janus Kinase 3)

JAK3 mutation

aspirin

2ms

Landscape analysis of breast cancer ovarian metastases reveals biology and potential therapeutic targets (SABCS 2024)

Our study provides the largest comprehensive characterization of ovarian metastases in patients with breast cancer. It not only deepens our understanding of ILC ovarian metastasis but provides the foundation for future studies aimed at improved prevention and treatment of breast cancer metastasis to the ovary.

2 months ago

HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • RUNX1 (RUNX Family Transcription Factor 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • KMT2C (Lysine Methyltransferase 2C) • CDH1 (Cadherin 1) • JAK3 (Janus Kinase 3) • FOXA1 (Forkhead Box A1) • PI3K (Phosphoinositide 3-kinases)

TP53 mutation • PIK3CA mutation • ERBB3 mutation • CDH1 mutation • JAK3 mutation

FoundationOne® CDx

2ms

Ruxolitinib combined with venetoclax and azacitidine in the treatment of refractory T-ALL patients with JAK1, JAK3, and STAT5B gene mutations: a case report and literature review (PubMed, Zhonghua Xue Ye Xue Za Zhi)

Notably, pleural effusion and mediastinal mass significantly improved the post-chest cavity infusion of dexamethasone combined with etoposide at the same stage. The patient also underwent allogeneic hematopoietic stem cell transplantation upon achieving bone marrow remission and was followed up until January 2024. Ruxolitinib combined with venetoclax and azacytidine has shown promising efficacy and safety in treating refractory T-ALL harboring the JAK1, JAK3, and STAT5B mutations, providing a novel therapeutic approach for such patients.

2 months ago

Review • Journal

JAK1 (Janus Kinase 1) • JAK3 (Janus Kinase 3) • STAT5B (Signal Transducer And Activator Of Transcription 5B)

JAK3 mutation

Venclexta (venetoclax) • azacitidine • Jakafi (ruxolitinib) • etoposide IV • dexamethasone

2ms

Identification of mutations in canine oral mucosal melanomas by exome sequencing and comparison with human melanomas. (PubMed, Sci Rep)

These mutations were categorized based on the gene functions. The identification of these mutations provides critical insights that can pave the way for the development of novel therapeutic strategies for both canine and human OMM, offering hope for more effective treatments in the future.

2 months ago

Clinical • Journal

NOTCH1 (Notch 1) • LRP1B (LDL Receptor Related Protein 1B) • EP300 (E1A binding protein p300) • JAK3 (Janus Kinase 3) • NCOR1 (Nuclear Receptor Corepressor 1) • FAT4 (FAT Atypical Cadherin 4)

JAK3 mutation

3ms

Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer. (PubMed, Bioorg Med Chem)

We have identified 20, 21 and 23 as potent mutant EGFR inhibitors (≤20 nM), with comparable or better selectivity over WT EGFR, and lower activity at JAK3, than Osimertinib or Rociletinib. Compounds 21 displayed the best combination of EGFR mutant activity, JAK3 selectivity, cellular activity and physicochemical properties. Finally, kinetic studies on 21 were performed, confirming a covalent mechanism of action at EGFR.

3 months ago

Journal

JAK3 (Janus Kinase 3)

EGFR mutation • EGFR L858R • EGFR T790M • EGFR wild-type • EGFR overexpression • JAK3 mutation

Tagrisso (osimertinib) • Xegafri (rociletinib)

3ms

Clinical and genetic profile of Chinese patients with indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract. (PubMed, Neoplasia)

"Watch and wait" therapy was preferable to intense chemotherapy. Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

3 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • JAK3 (Janus Kinase 3) • SH2B3 (SH2B Adaptor Protein 3)

KRAS mutation • BRAF mutation • JAK3 mutation

7ms

Keratinocytes present Staphylococcus aureus enterotoxins and promote malignant and non-malignant T cell proliferation in cutaneous T cell lymphoma. (PubMed, J Invest Dermatol)

In conclusion, we show that, upon exposure to patient-derived S. aureus and SE, keratinocytes stimulate IL-2Rγ/JAK3-dependent proliferation of malignant and non-malignant T-cells in an environment with non-malignant T-cells. These findings suggest that keratinocytes in the TME play a key role in S. aureus mediated disease activity in CTCL.

7 months ago

Journal

IFNG (Interferon, gamma) • IL2 (Interleukin 2) • JAK3 (Janus Kinase 3)

IFNG expression • JAK3 mutation

8ms

Treatment patterns, clinical outcomes and gene mutation characteristics of hepatitis B virus-associated mantle cell lymphoma. (PubMed, Hematol Oncol)

The HD-AraC (high-dose cytarabine) regimen was the main first-line induction regimen for younger HBsAg+ patients, and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) were used for elderly patients. HBsAg seropositivity was associated with a significantly shorter PFS than HBsAg seronegativity when patients were treated with rituximab or CHOP-based regimens...Among the 74 patients who underwent targeted deep sequencing (TDS), the nonsynonymous mutation load of HBsAg+ MCL patients was greater than that of HBsAg- MCL patients. HDAC1, TRAF5, FGFR4, SMAD2, JAK3, SMC1A, ZAP70, BLM, CDK12, PLCG2, SMO, TP63, NF1, PTPR, EPHA2, RPTOR and FIP1L1 were significantly enriched in HBsAg+ MCL patients.

8 months ago

Clinical data • Journal • Tumor mutational burden

TMB (Tumor Mutational Burden) • NF1 (Neurofibromin 1) • FGFR4 (Fibroblast growth factor receptor 4) • CDK12 (Cyclin dependent kinase 12) • PLCG2 (Phospholipase C Gamma 2) • FIP1L1 (Factor Interacting With PAPOLA And CPSF1) • JAK3 (Janus Kinase 3) • HDAC1 (Histone Deacetylase 1) • TP63 (Tumor protein 63) • SMAD2 (SMAD Family Member 2) • SMC1A (Structural Maintenance Of Chromosomes 1A)

BLM mutation • JAK3 mutation

Rituxan (rituximab) • cytarabine • doxorubicin hydrochloride • cyclophosphamide • vincristine

8ms

Analysis of mutation profiles in extranodal NK/T-cell lymphoma: clinical and prognostic correlations. (PubMed, Ann Hematol)

When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.

8 months ago

Journal

MCL1 (Myeloid cell leukemia 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • JAK3 (Janus Kinase 3) • PIM1 (Pim-1 Proto-Oncogene) • LIFR (LIF Receptor Subunit Alpha)

JAK3 mutation

9ms

Clinicopathological and molecular genetic alterations in monomorphic-epitheliotropic intestinal T-cell lymphoma of the small intestine. (PubMed, Eur J Med Res)

Our findings demonstrate that mutations in JAK3 and STAT5B of the JAK/STAT pathway and inactivation of the oncogene SETD2 markedly contribute to the lymphomagenesis of MEITL.

9 months ago

Journal • IO biomarker

TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD8 (cluster of differentiation 8) • BCOR (BCL6 Corepressor) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • JAK3 (Janus Kinase 3) • NCAM1 (Neural cell adhesion molecule 1) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • ITGAE (Integrin Subunit Alpha E) • SPN (Sialophorin)

TP53 mutation • CD8 expression • BCOR mutation • JAK3 mutation • SETD2 mutation

9ms

Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency. (PubMed, Int J Mol Sci)

The structure, function and impacts of both GOF and LOF mutations of JAK3 are highly conserved, making animal models highly informative. This review details the biology of JAK3 and the impact of its perturbation in immune cell-related diseases, including relevant animal studies.

9 months ago

Review • Journal • Immune cell

JAK3 (Janus Kinase 3)

JAK3 mutation

9ms

SYNERGY-AI: Artificial Intelligence Based Precision Oncology Clinical Trial Matching and Registry (clinicaltrials.gov)

P=N/A, N=50000, Recruiting, Massive Bio, Inc. | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

9 months ago

Trial completion date • Trial primary completion date

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • RB1 (RB Transcriptional Corepressor 1) • CLDN18 (Claudin 18) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • NRG1 (Neuregulin 1) • POLE (DNA Polymerase Epsilon) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PD-1 (Programmed cell death 1) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1) • KDR (Kinase insert domain receptor) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • VEGFA (Vascular endothelial growth factor A) • BCL6 (B-cell CLL/lymphoma 6) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • PTCH1 (Patched 1) • FGFR4 (Fibroblast growth factor receptor 4) • MSH6 (MutS homolog 6) • CDK4 (Cyclin-dependent kinase 4) • MSH2 (MutS Homolog 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • ATRX (ATRX Chromatin Remodeler) • BRCA (Breast cancer early onset) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase) • TSC2 (TSC complex subunit 2) • CHEK2 (Checkpoint kinase 2) • PD-L2 (Programmed Cell Death 1 Ligand 2) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • JAK1 (Janus Kinase 1) • FANCA (FA Complementation Group A) • TSC1 (TSC complex subunit 1) • MDM4 (The mouse double minute 4) • POLD1 (DNA Polymerase Delta 1) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • AURKA (Aurora kinase A) • JAK3 (Janus Kinase 3) • RICTOR (RPTOR Independent Companion Of MTOR Complex 2) • CHEK1 (Checkpoint kinase 1) • GATA6 (GATA Binding Protein 6) • MSH3 (MutS Homolog 3) • TGFBR2 (Transforming Growth Factor Beta Receptor 2) • GNAS (GNAS Complex Locus) • MYCL (MYCL Proto-Oncogene BHLH Transcription Factor) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3) • CSF1R (Colony stimulating factor 1 receptor) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • ERCC4 (ERCC Excision Repair 4, Endonuclease Catalytic Subunit) • HDAC1 (Histone Deacetylase 1) • PRDM1 (PR/SET Domain 1) • ZNF217 (Zinc Finger Protein 217) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • GATA3 (GATA binding protein 3) • PARP2 (Poly(ADP-Ribose) Polymerase 2) • PARP3 (Poly(ADP-Ribose) Polymerase Family Member 3) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A) • ACVR1B (Activin A Receptor Type 1B) • ZNF703 (Zinc Finger Protein 703)

HER-2 mutation • BAP1 mutation • AKT1 mutation • FGFR3 fusion • JAK3 mutation

9ms

Integrated analysis of transcriptome and genome variations in pediatric T cell acute lymphoblastic leukemia: data from north Indian tertiary care center. (PubMed, BMC Cancer)

Overall, the present study demonstrates the frequencies of transcriptomic and genetic alterations from Indian cohort of pediatric T-ALL and is a salient addition to current genomics data sets available in T-ALL.

9 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • MTAP (Methylthioadenosine Phosphorylase) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • ETV6 (ETS Variant Transcription Factor 6) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • JAK3 (Janus Kinase 3) • PHF6 (PHD Finger Protein 6) • SPI1 (Spi-1 Proto-Oncogene) • LPAR6 (Lysophosphatidic Acid Receptor 6) • NKX3-1 (NK3 homeobox 1) • RAG1 (Recombination Activating 1) • TCF7 (Transcription Factor 7)

KRAS mutation • NOTCH1 mutation • CDKN2A deletion • JAK3 mutation • KRAS deletion

10ms

A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. (PubMed, Haematologica)

By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies.

10 months ago

Journal

ASXL1 (ASXL Transcriptional Regulator 1) • JAK3 (Janus Kinase 3) • SETBP1 (SET Binding Protein 1)

RAS mutation • ASXL1 mutation • JAK3 mutation

10ms

N-Acetylcysteine alters disease progression and increases Janus Kinase mutation frequency in a mouse model of precursor B cell acute lymphoblastic leukemia. (PubMed, J Pharmacol Exp Ther)

These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. Significance Statement In a mouse model of precursor B cell acute lymphoblastic leukemia associated with high levels of ROS, treatment with N-acetylcysteine did not delay disease progression, but instead selected for leukemic clones with increased frequency of activating R653H mutations in Janus Kinase 3.

10 months ago

Preclinical • Journal

PTEN (Phosphatase and tensin homolog) • JAK3 (Janus Kinase 3)

JAK3 mutation

11ms

Idiopathic erythrocytosis: a germline disease? (PubMed, Clin Exp Med)

We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.

11 months ago

Journal • Tumor mutational burden

TMB (Tumor Mutational Burden) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • WT1 (WT1 Transcription Factor) • EPAS1 (Endothelial PAS domain protein 1) • JAK3 (Janus Kinase 3)

TMB-H • DNMT3A mutation • TMB-L • JAK2 V617F • JAK2 mutation • JAK3 mutation • HIF1A P582S

OncoPanel™ Assay

12ms

Genomic and transcriptomic characteristics of 12 novel primary cell lines derived from three patients with cholangiocarcinoma. (PubMed, Genomics)

Furthermore, the drug-sensitivity results revealed that the PDPCs exhibited different responses to the six commonly used compounds. Our findings indicate that the established PDPCs can serve as novel in vitro reliable models to provide a crucial molecular basis for improving the understanding of tumorigenesis and its treatment.

12 months ago

Preclinical • Journal

TP53 (Tumor protein P53) • KMT2C (Lysine Methyltransferase 2C) • JAK3 (Janus Kinase 3) • PDP1 (Pyruvate Dehydrogenase Phosphatase Catalytic Subunit 1)

TP53 mutation • JAK3 mutation

1year

In vitro and in vivo modelling of mutant JAK3/STAT5 signaling in leukemia. (PubMed, Heliyon)

Here we describe the important steps required to generate retroviral particles for the stable expression of mutant JAK3 constructs that induce constitutive JAK/STAT signaling. These are subsequently used for the viral transduction of the IL-3 cytokine-dependent Ba/F3 cell line or murine hematopoietic stem and progenitor cells (HSPCs) for in vitro and in vivo modelling of cytokine-independent growth or leukemia initiation respectively.

1 year ago

Preclinical • Journal

JAK3 (Janus Kinase 3) • IL7 (Interleukin 7) • STAT5A (Signal Transducer And Activator Of Transcription 5A)

JAK3 mutation • STAT5A mutation

1year

The JAK3 mutation reveals oncogenic potential and resistance to ruxolitinib. (PubMed, Mol Carcinog)

Notably, JAK3 not only promotes constitutive activation of the JAK/STAT pathway in the absence of cytokines and growth factors, as is the case for other JAK3 mutations that have been functionally characterized as oncogenic, but also functions independently of JAK1 and IL2RG, resulting in high oncogenic potential as well as resistance to ruxolitinib. Our results indicate that ruxolitinib may not be efficient for future patients bearing the JAK3 mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.

1 year ago

Journal

JAK1 (Janus Kinase 1) • JAK3 (Janus Kinase 3) • IL2RG (Interleukin 2 Receptor Subunit Gamma)

JAK3 mutation

Jakafi (ruxolitinib) • tofacitinib

1year

Identification of prognostic biomarkers for cervical cancer based on programmed cell death-related genes and assessment of their immune profile and response to drug therapy. (PubMed, J Gene Med)

In the present study, we first found that PCD-related gene expression patterns were correlated with clinical features of CESC patients, which predicts the feasibility of subsequent mining of prognostic features based on these genes. The five-PCD-associated-gene prognostic model showed good assessment ability in predicting patient prognosis, immune response and drug-sensitive response, and provided guidance for the elucidation of the mechanism by which PCD affects CESC, as well as for the clinical targeting of drugs.

1 year ago

Journal • IO biomarker

JAK3 (Janus Kinase 3) • CA9 (Carbonic anhydrase 9) • SERPINE1 (Serpin Family E Member 1) • CX3CL1 (C-X3-C Motif Chemokine Ligand 1)

JAK3 mutation

SCH772984 • BI2536

1year

CAR+ T-Cell Lymphoma Post Ciltacabtagene Autoleucel Therapy for Relapsed Refractory Multiple Myeloma (ASH 2023)

26) vs standard of care in lenalidomide-refractory patients with multiple myeloma and 1-3 prior lines of therapy...The patient received CHOEP-21 (cyclophosphamide-doxorubicin-vincristine-prednisone-etoposide) and achieved metabolic CR but relapsed soon after treatment was stopped. Subsequent treatment with gemcitabine-dexamethasone-cisplatin-alemtuzumab was followed by consolidation with fludarabine plus melphalan and matched allogeneic stem cell transplant... To our knowledge, this is the first case of CAR+ TCL occurring after infusion of a CAR-T therapy produced via lentiviral transduction (cilta-cel). This rare malignancy was potentially driven by genetic mutations (e. g.

1 year ago

Tumor mutational burden • IO biomarker

ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • CD8 (cluster of differentiation 8) • TNFRSF8 (TNF Receptor Superfamily Member 8) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD34 (CD34 molecule) • JAK3 (Janus Kinase 3) • NCAM1 (Neural cell adhesion molecule 1) • CD7 (CD7 Molecule) • CD2 (CD2 Molecule) • NFKB2 (Nuclear Factor Kappa B Subunit 2)

TMB-L • TET2 mutation • JAK3 mutation

cisplatin • gemcitabine • lenalidomide • doxorubicin hydrochloride • cyclophosphamide • etoposide IV • Campath (alemtuzumab) • vincristine • prednisone • dexamethasone • melphalan • fludarabine IV • Carvykti (ciltacabtagene autoleucel)

1year

Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies. (PubMed, Int J Mol Sci)

FERM domains of JAK1 and JAK3 are identified as a hot spot for hematologic malignancies. Herein, we propose new allosteric surfaces for targeting hyperactive JAK dimers.

1 year ago

Journal

JAK1 (Janus Kinase 1) • IL2 (Interleukin 2) • JAK3 (Janus Kinase 3)

JAK3 mutation

1year

New JAK3-INSL3 Fusion Transcript-An Oncogenic Event in Cutaneous T-Cell Lymphoma. (PubMed, Cells)

In NSG xenograft mice, smaller tumor sizes were observed in MJ cells transduced with specific shRNAs than cells transduced with controls. Our results suggest that the newly identified JAK3-INSL3 fusion transcript confers an oncogenic event in CTCL.

1 year ago

Journal

JAK3 (Janus Kinase 3)

JAK3 mutation

1year

Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma:Pathological Phenotype and Genetic Mutation Analysis of 12 Patients (ASH 2023)

Our results show that MEITL is extremely rare, accounting for only 2.4% of all lymphomas involving the intestines. Patients with MEITL have a poor prognosis, with a median OS of less than six months. However, early elective surgery can significantly improve patient survival.

1 year ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • CD20 (Membrane Spanning 4-Domains A1) • JAK2 (Janus kinase 2) • CD8 (cluster of differentiation 8) • TNFRSF8 (TNF Receptor Superfamily Member 8) • CREBBP (CREB binding protein) • BCOR (BCL6 Corepressor) • JAK1 (Janus Kinase 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • CD4 (CD4 Molecule) • EP300 (E1A binding protein p300) • JAK3 (Janus Kinase 3) • NCAM1 (Neural cell adhesion molecule 1) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • GZMB (Granzyme B) • SOCS1 (Suppressor Of Cytokine Signaling 1) • CHD2 (Chromodomain Helicase DNA Binding Protein 2) • TIA1 (TIA1 Cytotoxic Granule Associated RNA Binding Protein)

KRAS mutation • NRAS mutation • TNFRSF8 expression • CD20 expression • CD8 expression • NCAM1 expression • JAK3 mutation • CD4 expression

1year

Bone Marrow, Laboratory, and Clinical Features in Pediatric Patients with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM) (ASH 2023)

Germline mutation in RUNX1 should be considered in pediatric patients with thrombocytopenia and/or abnormal platelet function and a hypocellular marrow with or without dysmegakaryopoiesis. Dysmegakaryopoiesis in the setting of RUNX1-FPDMM should not be overinterpreted as pediatric MDS without other supporting criteria such as MDS-defining cytogenetic/molecular abnormalities, multilineage dysplasia, or increased blasts. Patients with large deletions in RUNX1 may be missed on routine NGS testing hence proper germline testing in an experienced laboratory is recommended if suspicion is high.

1 year ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • CD8 (cluster of differentiation 8) • RUNX1 (RUNX Family Transcription Factor 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • BCOR (BCL6 Corepressor) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD4 (CD4 Molecule) • JAK3 (Janus Kinase 3) • CD7 (CD7 Molecule) • EBF1 (EBF Transcription Factor 1) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • KDM6B (Lysine Demethylase 6B) • PRMT7 (Protein Arginine Methyltransferase 7) • GJB2 (Gap Junction Protein Beta 2)

KRAS mutation • RUNX1 mutation • BCOR mutation • JAK3 mutation • CD123 expression

1year

Genomic Landscape of Pediatric Non-Down's Syndrome Acute Megakaryoblastic Leukemia in China (ASH 2023)

We further revealed a distinct mutation profile between AMKL and non-AMKL and shed light on association between driver aberrations and clinical outcomes. These findings revealed non-DS-AMKL as a heterogenous disease, and suggested the importance of exploration of risk-stratification and targeted therapy in different mutations driven cases.

1 year ago

Clinical • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CSF3R (Colony Stimulating Factor 3 Receptor) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • JAK3 (Janus Kinase 3) • FUS (FUS RNA Binding Protein) • GATA2 (GATA Binding Protein 2) • CBFA2T3 (CBFA2/RUNX1 Partner Transcriptional Co-Repressor 3) • GATA1 (GATA Binding Protein 1) • GLIS2 (GLIS Family Zinc Finger 2) • KDM5A (Lysine Demethylase 5A) • GNA12 (G Protein Subunit Alpha 12) • RBM15 (RNA Binding Motif Protein 15)

NRAS G13 • JAK3 mutation

1year

Error-Corrected Next-Generation Sequencing Provides a Comprehensive Overview of the Subclonal Mutation Landscape and Its Prognostic Implications in Juvenile Myelomonocytic Leukemia (ASH 2023)

We successfully performed error-corrected NGS to assess comprehensive subclonal secondary mutational profiles, including very low VAF variants. The presence of subclonal mutations, particularly in RAS pathway genes, was associated with poor OS. These findings provide important information for appropriate risk stratification, which will contribute to the implementation of precision medicine for patients with JMML.

1 year ago

Next-generation sequencing

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • JAK3 (Janus Kinase 3) • SETBP1 (SET Binding Protein 1) • SH2B3 (SH2B Adaptor Protein 3) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

KRAS mutation • RAS mutation • CBL mutation • JAK3 mutation • ZRSR2 mutation

1year

Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma (ASH 2023)

Low mRNA expression of PHLPP2 predicted poor prognosis (p=.03) and engineered PHLPP2 loss showed enhanced PI(3)K activation and FOXO1 inactivation in CD4+ T-cells in-vitro. Thus, we defined the genomic landscape for AITL, which is largely characterized by epigenetic alterations, TCR signaling and PI3K/AKT dysregulation, which may be amenable for therapeutic targeting.

1 year ago

IO biomarker • Omic analysis

PTEN (Phosphatase and tensin homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CD20 (Membrane Spanning 4-Domains A1) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2D (Lysine Methyltransferase 2D) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CD163 (CD163 Molecule) • CD4 (CD4 Molecule) • JAK3 (Janus Kinase 3) • RHOA (Ras homolog family member A) • CD68 (CD68 Molecule) • PHLPP1 (PH Domain And Leucine Rich Repeat Protein Phosphatase 1) • SOCS1 (Suppressor Of Cytokine Signaling 1) • STAT1 (Signal Transducer And Activator Of Transcription 1) • VAV1 (Vav Guanine Nucleotide Exchange Factor 1) • HLPP2 (PH Domain And Leucine Rich Repeat Protein Phosphatase 2) • PHLPP2 (PH Domain And Leucine Rich Repeat Protein Phosphatase 2)

IDH2 mutation • DNMT3A mutation • TET2 mutation • KMT2D mutation • JAK3 mutation • IDH2 R172 • RHOA G17V

1year

Inflammatory Signatures Define a New High-Risk T-Lineage ALL Subtype (ASH 2023)

Finally, we demonstrate that inflammatory, but not non-inflammatory, T-lineage ALL cells are significantly more sensitive to BCL-2 inhibitor venetoclax ex vivo (Figure 1B). Overall, our study has identified a new subtype of T-lineage ALL defined by an early arrest in T-cell development, inflammatory signaling, a unique mutational landscape, sensitivity to venetoclax, and an association with adverse clinical parameters.

1 year ago

IO biomarker

NRAS (Neuroblastoma RAS viral oncogene homolog) • WT1 (WT1 Transcription Factor) • JAK3 (Janus Kinase 3) • IL18 (Interleukin 18) • IL1B (Interleukin 1, beta)

JAK3 mutation

Venclexta (venetoclax)

1year

Efficacy of Demethylated Drug Combine with Low Dose Chemotherapy in Juvenile Myelomonocytic Leukemia (ASH 2023)

All patients were given Demethylated drug in combination with low-dose chemotherapy, 10 patients decitabine at a dose of 20 mg/m2 for 5 days, supplemented with cytarabine (50-100 mg/m2×3~5 days), and /or etoposide (50 mg/m2×3~5 days), 6 patients Azacytidine at a dose of 75mg/m2 for 7 days combined with homoharringtonine 2mg/m2 for 5-7 days. Demethylated drug in combination with low-dose chemotherapy could reduce JMML patients' tumor burden, improve the general condition, and obtain a clinical response rate of 81.8% after 3 cycles therapy. Therefore, such a combination regimen could be used as a therapeutic option for JMML before HSCT.

1 year ago

Clinical

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ARID1A (AT-rich interaction domain 1A) • NF1 (Neurofibromin 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • JAK3 (Janus Kinase 3) • SETBP1 (SET Binding Protein 1) • SH2B3 (SH2B Adaptor Protein 3)

KRAS mutation • NRAS mutation • ARID1A mutation • NF1 mutation • ASXL1 mutation • PTPN11 mutation • SRSF2 mutation • SETBP1 mutation • JAK3 mutation

cytarabine • azacitidine • etoposide IV • decitabine • Synribo (omacetaxine mepesuccinate)

1year

Pax5 Heterozygosity Affects B-Cell Differentiation and Generates a Deregulated Precursor Population in the Bone Marrow (ASH 2023)

In summary, we deeply characterized how reduced Pax5 transcriptional activity in the BM generates a predisposed precursor B-cell environment, which is susceptibility for malignant transformation. These findings are important for understanding the molecular mechanisms to prevent or treat a significant proportion of childhood BCP-ALLs.

1 year ago

Clinical

JAK1 (Janus Kinase 1) • PAX5 (Paired Box 5) • IL2RA (Interleukin 2 receptor, alpha) • JAK3 (Janus Kinase 3) • LYN (LYN Proto-Oncogene Src Family Tyrosine Kinase) • CD79A (CD79a Molecule) • IL7 (Interleukin 7) • ISG20 (Interferon Stimulated Exonuclease Gene 20)

JAK3 mutation

1year

CD7 Chimeric Antigen Receptor T-Cell Therapy Bridging to Allogeneic Hematopoietic Stem Cell Transplantation Remarkably Improved Long-Term Disease-Free Survival in Refractory/Relapsed T-Cell Acute Lymphoblastic Leukemia/Lymphoma (ASH 2023)

Myeloablative conditioning regimens with either total body irradiation (TBI)/fludarabine (51, 56.7%) based or busulfan/fludarabine (39, 43.3%) based were applied...Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis... Our study has demonstrated that CD7 CART followed by allo-HSCT has remarkably improved long-term DFS for chemotherapy-resistant T-ALL/LBL, and achieved comparable results in safety and efficacy with chemotherapy-sensitive disease post-transplant. Our study has also shown the profiles of somatic and germline gene mutations in r/r T-ALL/LBL, and identified some positive and negative impact factors for prognosis after transplant in this setting.

1 year ago

CAR T-Cell Therapy

TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NOTCH1 (Notch 1) • JAK1 (Janus Kinase 1) • EP300 (E1A binding protein p300) • JAK3 (Janus Kinase 3) • CD7 (CD7 Molecule) • MED12 (Mediator Complex Subunit 12)

TP53 mutation • ATM mutation • NOTCH1 mutation • JAK3 mutation • EP300 mutation

methotrexate • fludarabine IV • busulfan • cyclosporine

1year

Case Report: Aggressive NK Cell Leukemia in a 58-Year-Old Female Patient - Use of an Individualized Treatment Approach with Venetoclax/Ruxolitinib (DGHO 2023)

First-line treatment consisted of polychemotherapy according to the SMILE protocol (methotrexate, dexamethasone, ifosfamide, etoposide phosphate, PEG-asparaginase), but the patient relapsed within three weeks. Salvage therapy was started according to the GMALL protocol with prephase therapy (cyclophosphamide and dexamethasone) followed by induction I (idarubicin, vincristine and dexamethasone)... ANKL is a rare and aggressive disease associated with a poor prognosis. In line with this, our patient did not show durable responses to polychemotherapy including MTX, L-asparaginase, alkylating agents, and anthracyclines. Despite post-remission treatment with allo-HSCT and a personalized medicine approach based on treatment guided by mutational analysis, the patient showed rapid progression and ultimately succumbed to the disease.

1 year ago

Clinical • IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • JAK3 (Janus Kinase 3)

JAK3 mutation

Venclexta (venetoclax) • Jakafi (ruxolitinib) • cyclophosphamide • ifosfamide • etoposide IV • methotrexate • vincristine • idarubicin hydrochloride

1year

Rapidly progressive primary cutaneous gamma delta T-cell lymphoma with FYN gene alteration (ASDP 2023)

At a 4-week follow-up after diagnosis, a new leukocytosis with lymphocytosis was identified, and flow cytometric analysis was performed showing involvement by an increased abnormal γδ T-cell population with immunophenotype similar to the lymphoma involving the skin, consistent with rapid systemic progression of PCγδTCL. Poster type: Poster Defense

1 year ago

PD(L)-1 Biomarker • IO biomarker

TP53 (Tumor protein P53) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • PD-1 (Programmed cell death 1) • MYCN (MYCN Proto-Oncogene BHLH Transcription Factor) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2D (Lysine Methyltransferase 2D) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • STAT3 (Signal Transducer And Activator Of Transcription 3) • JAK3 (Janus Kinase 3) • TNFAIP3 (TNF Alpha Induced Protein 3) • CD5 (CD5 Molecule) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • SOCS1 (Suppressor Of Cytokine Signaling 1) • FYN (FYN Proto-Oncogene, Src Family Tyrosine Kinase)

TP53 mutation • JAK3 mutation

1year

A Diagnostic Challenge: An Intriguing Case of Persistent Lip Swelling Leading to the Diagnosis of Aggressive CD8 Positive Cytotoxic T-Cell Lymphoma (ASDP 2023)

The case suggests a mucocutaneous variant of primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma, highlighting the diagnostic challenges inherent in diagnostic dermatopathology. Poster type: Poster Defense

1 year ago

Clinical

TP53 (Tumor protein P53) • JAK2 (Janus kinase 2) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • JAK3 (Janus Kinase 3) • NCAM1 (Neural cell adhesion molecule 1) • CD7 (CD7 Molecule)

TP53 mutation • CD8 expression • CD8 positive • JAK3 mutation • JAK2 fusion

over1year

Intertumoral heterogeneity impacts oncolytic vesicular stomatitis virus efficacy in mouse pancreatic cancer cells. (PubMed, J Virol)

Also, we discovered that more VSV-permissive mouse PDAC cell lines harbor mutations in multiple important antiviral genes, such as TYK2, JAK2, and JAK3. Our study provides essential information about three model mouse PDAC cell lines and proposes a novel platform to study OV-based therapies against different PDACs in immunocompetent mice.

over 1 year ago

Preclinical • Journal • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • JAK2 (Janus kinase 2) • JAK3 (Janus Kinase 3) • TYK2 (Tyrosine Kinase 2) • PDX1 (Pancreatic And Duodenal Homeobox 1)

JAK3 mutation

over1year

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing. (PubMed, Front Pediatr)

Although T-ALL and T-LBL both originate from precursor T-cells and are considered different manifestations of the same disease and the outcome of T-LBL is favorable when using T-ALL-based chemotherapy, there are differences in the gene distribution between T-LBL and T-ALL. It seems that the PI3K-Akt signaling pathway and the USP34 gene play important roles in T-LBL, but medicines targeting the USP34 gene or the PI3K-Akt pathway may be invalid.

over 1 year ago

Journal • Metastases

NOTCH1 (Notch 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • JAK3 (Janus Kinase 3) • PHF6 (PHD Finger Protein 6) • USP34 (Ubiquitin Specific Peptidase 34)

NOTCH1 mutation • FBXW7 mutation • JAK3 mutation • PHF6 mutation

over1year

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation. (PubMed, Int J Mol Sci)

Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

over 1 year ago

Journal

JAK1 (Janus Kinase 1) • JAK3 (Janus Kinase 3) • STAT5B (Signal Transducer And Activator Of Transcription 5B)

JAK3 mutation