Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2V617F or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2V617F and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2R715T in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2R715T mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2R715T kinase. Similar to PV, the JAK2R715T native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2V617F PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2R715T gain-of-function mutation with many but not all comparable molecular features to JAK2V617F PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.
- MeSH
- aktivační mutace MeSH
- dospělí MeSH
- interferon alfa terapeutické užití MeSH
- Janus kinasa 2 * genetika MeSH
- lidé MeSH
- polycytemie * genetika farmakoterapie MeSH
- polycythaemia vera genetika farmakoterapie MeSH
- rodokmen MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
STAT1 gain-of-function (GOF) mutations underlie an inborn error of immunity hallmarked by chronic mucocutaneous candidiasis (CMC). Beyond the fungal susceptibility, attributed to Th17 failure, over half of the reported patients suffer from autoimmune manifestations, mechanism of which has not been explained yet. We hypothesized that the STAT1 mutations would affect dendritic cells' (DCs) properties and alter their inflammatory and tolerogenic functions. To test the hypothesis, we generated monocyte-derived DCs (moDCs) and tolerogenic DCs (tDCs). Functional and signaling studies, co-culture experiments and RNA sequencing demonstrated that STAT1 GOF DCs were profoundly altered in their phenotype and functions, characterized by loss of tolerogenic functions, proinflammatory skew and decreased capacity to induce Th17. Cytokine signaling, autophagy and metabolic processes were identified as the most prominently altered cellular processes. The results suggest that DCs are directly involved in STAT1 GOF-associated immune pathology, possibly contributing to both autoimmune manifestations and the failure of antifungal defense.
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
- MeSH
- aktivační mutace MeSH
- autoprotilátky * imunologie MeSH
- COVID-19 genetika imunologie MeSH
- epiteliální buňky štítné žlázy metabolismus patologie MeSH
- genetická predispozice k nemoci * MeSH
- heterozygot MeSH
- interferon typ I * antagonisté a inhibitory imunologie MeSH
- kinasa indukující NF-kappaB MeSH
- lidé MeSH
- mutace ztráty funkce MeSH
- NF-kappa B - podjednotka p52 nedostatek genetika MeSH
- NF-kappa B * nedostatek genetika MeSH
- protein AIRE MeSH
- proteiny I-kappa B nedostatek genetika MeSH
- thymus abnormality imunologie patologie MeSH
- virová pneumonie genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
V přehledovém článku jsou uvedena data ze studie CHRYSALIS týkající se účinné látky amivantamab v léčbě nemalobuněčného karcinomu plic s mutací genu pro receptor epidermálního růstového faktoru (epidermal growth factor receptor, EGFR), a to s inzercí v exonu 20. Na podkladě dosavadních prognostických faktorů jsou známa data o přežití z reálné praxe současné léčby. Primárním cílem ve studii byla celková četnost odpovědí, hodnocená nezávislou centrální revizní komisí. Jsou uvedeny výsledky hodnocení a účinnost u 89 pacientů, trvání léčebné odpovědi a protinádorová aktivita amivantamabu u všech studovaných subtypů mutací. Výsledky jsou prezentovány v tabulkách a grafech. Na podkladě výsledků studie CHRYSALIS byl amivantamab schválen Evropskou lékovou agenturou v prosinci 2021 k léčbě dospělých pacientů s pokročilým nemalobuněčným karcinomem plic s aktivační mutací, inzercí v exonu 20 EGFR, v monoterapii, po selhání léčby na bázi platiny.
This review article presents data from the CHRYSALIS study on the efficacy of amivantamab in treating non-smaii cell lung cancer with activating epidermal growth factor receptor (EGFR) mutations, specifically involving an insertion in exon 20. Known survival data from real-world practice based on current prognostic factors is included. The study’s primary endpoint was the overall response rate, assessed by an independent central review committee. The article details the evaluation results and efficacy in 89 patients, the duration of treatment response, and amivantamab’s antitumor activity across all studied mutation subtypes. Findings are presented in tables and graphs. Following the CHRYSALIS study results, the European Medicines Agency approved amivantamab in December 2021 for treating adult patients with advanced non-small cell lung cancer, specifically with activating EGFR mutations involving an insertion in exon 20, as a monotherapy following the failure of platinum-based treatment.
- Klíčová slova
- studie CHRYSALIS, amivantanab,
- MeSH
- aktivační mutace genetika MeSH
- epidermální růstový faktor antagonisté a inhibitory farmakologie genetika MeSH
- farmakoterapie * MeSH
- humanizované monoklonální protilátky farmakologie klasifikace terapeutické užití MeSH
- imunoglobulin G farmakologie klasifikace MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * diagnóza farmakoterapie MeSH
- nežádoucí účinky léčiv MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
- MeSH
- aktivační mutace MeSH
- autoimunita genetika MeSH
- dítě MeSH
- kohortové studie MeSH
- lidé MeSH
- lymfocyty MeSH
- mutace MeSH
- nemoci imunitního systému * MeSH
- proliferace buněk MeSH
- syndromy imunologické nedostatečnosti * genetika MeSH
- transkripční faktor STAT3 genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
STAT1 gain-of-function (GOF) mutations cause an inborn error of immunity with diverse phenotype ranging from chronic mucocutaneous candidiasis (CMC) to various non-infectious manifestations, the most precarious of which are autoimmunity and vascular complications. The pathogenesis centers around Th17 failure but is far from being understood. We hypothesized that neutrophils, whose functions have not been explored in the context of STAT1 GOF CMC yet, might be involved in the associated immunodysregulatory and vascular pathology. In a cohort of ten patients, we demonstrate that STAT1 GOF human ex-vivo peripheral blood neutrophils are immature and highly activated; have strong propensity for degranulation, NETosis, and platelet-neutrophil aggregation; and display marked inflammatory bias. STAT1 GOF neutrophils exhibit increased basal STAT1 phosphorylation and expression of IFN stimulated genes, but contrary to other immune cells, STAT1 GOF neutrophils do not display hyperphosphorylation of STAT1 molecule upon stimulation with IFNs. The patient treatment with JAKinib ruxolitinib does not ameliorate the observed neutrophil aberrations. To our knowledge, this is the first work describing features of peripheral neutrophils in STAT1 GOF CMC. The presented data suggest that neutrophils may contribute to the immune pathophysiology of the STAT1 GOF CMC.
- MeSH
- aktivační mutace * MeSH
- autoimunita MeSH
- fenotyp MeSH
- fosforylace MeSH
- kandidóza chronická mukokutánní * farmakoterapie genetika MeSH
- lidé MeSH
- neutrofily metabolismus MeSH
- transkripční faktor STAT1 * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Aktivační mutace genu KRAS (Kirsten rat sarcoma viral oncogene homologue) lze detekovat u cca 25-30 % nemalobuněčných plicních karcinomů (non-small cell lung cancer, NSCLC), představuje nejčastější genetickou aberaci u těchto pacientů. Nejčastěji je detekována mutace KRAS p.G12Cs frekvencí cca 13 %. Sotorasib je specifický ireverzibilní inhibitor proteinu KRAS G12C. V rámci studie CodeBreaK 100 byl prokázán významný přínos léčby sotorasibem u pacientů s KRAS G12C NSCLC. Bezpečnostní profil sotorasibu je příznivý.
An activating mutation of the KRAS gene (Kirsten rat sarcoma viral oncogene homologue) is detected in approximately 25 to 30% of NSCLC and represents the most common genetic aberration in these patients. The most frequently detected mutation is KRAS p.G12C with a frequency of approximately 13%. Sotorasib is a specific irreversible inhibitor of the KRAS G12C protein. In the CodeBreaK 100 trial, there was a significant benefit of sotorasib treatment in patients with KRAS G12C NSCLC. The safety profile of sotorasib is favorable.
- Klíčová slova
- sotorasib, studie CodeBreaK 100,
- MeSH
- aktivační mutace účinky léků MeSH
- doba přežití bez progrese choroby MeSH
- geny ras * účinky léků MeSH
- inhibitory syntézy proteinů farmakologie škodlivé účinky terapeutické užití MeSH
- klinické zkoušky, fáze II jako téma MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * farmakoterapie genetika MeSH
- protinádorové látky farmakologie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- aktivační mutace * MeSH
- inflamasomy MeSH
- lidé MeSH
- proteiny vázající vápník genetika MeSH
- signální adaptorové proteiny CARD genetika MeSH
- zánět * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- MeSH
- aktivační mutace imunologie MeSH
- COVID-19 imunologie MeSH
- imunogenicita vakcíny imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mRNA vakcíny škodlivé účinky imunologie MeSH
- protilátky virové imunologie MeSH
- SARS-CoV-2 imunologie MeSH
- syntetické vakcíny škodlivé účinky imunologie MeSH
- transkripční faktor STAT1 imunologie MeSH
- vakcíny proti COVID-19 škodlivé účinky imunologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
