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1.
Medicine (Baltimore) ; 99(34): e21757, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846801

RESUMO

RATIONALE: Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition, which mainly manifests as headaches, seizures, and focal neurological deficits. JAK2 mutation in myeloproliferative diseases increases the risk of CVT. PATIENT CONCERNS: This 40-year-old woman suffered from rapidly progressive cognitive impairment and limb weakness. Her symptoms worsened while being treated with mannitol with the diagnose of cerebral hemorrhage. DIAGNOSIS: The patient was diagnosed with CVT and multiple intracranial hemorrhage caused by JAK2 V617F mutation-positive primary myelofibrosis by neuroimage and whole-exome sequencing. INTERVENTION: She received low-molecular-weight heparin sodium 3800 IU twice a day followed by oral anticoagulant therapy. OUTCOMES: The patient showed full recovery from limb weakness and in the follow-up period she noticed no change in her memory. LESSONS: Clinicians should be aware of the possibility of the JAK2 V617F mutation in CVT patients without known causes or risk factors.


Assuntos
Disfunção Cognitiva/etiologia , Trombose Intracraniana/etiologia , Janus Quinase 2/genética , Mielofibrose Primária/complicações , Trombose Venosa/etiologia , Adulto , Anticoagulantes/uso terapêutico , Feminino , Humanos , Trombose Intracraniana/tratamento farmacológico , Mielofibrose Primária/genética , Trombose Venosa/tratamento farmacológico
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1321-1325, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798420

RESUMO

OBJECTIVE: To investigate the clinical characteristics of essential thrombocytopenia (ET) patients with positive mutations including JAK2, CALR, MPL, or negative mutations. METHODS: A total of 66 newly diagnosed ET cases from January 2016 to December 2018 in Department of Hematology, Huaian No.1 People's Hospital affiliated to Nanjing Medical University were analyzed. Statistical analysis data included the patient's sex, age, symptoms, thrombosis and embolism events, spleen omegaly, platelet count (Plt), leukocyte (WBC) count, hemoglobin (Hb), fibrinogen (FIB), thrombus elastic diagram (TEG), serum potassium, blood glucose (GLU), lactate dehydrogenase (LDH), JAK2, CALR and MPL mutations, treatment options, and efficacy. RESULTS: All the patients were not MPL-positive, and divided in three groups: JAK2 mutation (46 cases, 69.7%), CALR mutation (9 cases, 13.6%) and gene negative mutation (11 cases, 16.7%) group. The average age of patients in the JAK2 mutation group was 63.2 years old, and significantly higher than that in the CALR mutation group (51.8 year) and gene negative group (50.2 year) (P<0.05). Compared with the JAK2 mutation group and gene negative group, the CALR mutation group had lower WBC count (6.3×109/L vs 13.79×109/L) (P=0.003) (6.3×109/L vs 9.70×109/L) (P=0.009). Also the Hb level of patients in CALR mutation group was lower than the JAK2 mutation group (121.22 g/L vs 136.2 g/L) (P=0.036). However, there was higher tumor burden in the CALR mutation group, compared with the gene negative mutation group (300.11 U/L vs 227.4 U/L) (P=0. 033). There was no significant difference among the three groups, such as the Plt counts, serum potassium level, GLU level and FIB level (P>0.05). In addition, thrombus and embolism appeared in 30.3% (20/66) cases. 18.2% (12/66) cases were complicated with hyperkalemia, which significantly correlated with Plt counts (r=0.518). TEG was performed in 34 patients, of which 41.2% (14/34) had abnormal TEG and 55.9% (19/34) were accompanied by Plt count > 1 000 ×109/L, but there was no significant correlation between them (r=0.134). After routine clinical treatment, all the 66 cases achieved partial or complete hematological remission, but the disease usually repeated. Until now 4.5% (3/66) cases had been converted to myelofibrosis (MF) all with JAK2 mutation, but without advancing to acute myeloid leukemia. CONCLUSION: ET patients with JAK2 mutation have higher incidence, moreover were in older age. However, the patients with CALR mutations display lower WBC count and Hb level, but higher tumor burden. In short, the multiple gene mutations of ET showed different clinical features closely relates with the prognosis, thus providing guidance for the clinical diagnosis and treatment.


Assuntos
Mielofibrose Primária , Trombocitemia Essencial , Trombocitopenia , Idoso , Calreticulina/genética , Humanos , Janus Quinase 2/genética , Pessoa de Meia-Idade , Mutação
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1326-1331, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798421

RESUMO

OBJECTIVE: To investigate the clinical characteristics, laboratorial and bone marrow pathological features of primary thrombocytopenia (ET) patients with different mutations of CALR, JAK2 and MPL genes. METHODS: The chinical data of 120 cases of ET in Jiangsu provincial people's hospital/ The First Affiliated Hospital of Nanjing Medical University from January 2015 to December 2017 were collected and analyzed, including 76 cases with JAK2 gene mutation, 40 cases with CALR gene mutation, 2 cases with MPL gene mutations, 2 cases without gene mutation. RESULTS: Among the ET patients, compared with the JAK2 gene mutation, CALR gene mutation showed statistically significant deareament of white blood cells and hemoglobin (P=0.001, P=0.01) and the male platelets in CALR group showed significant increament (P=0.04). Fourthermore, the average number of megakaryocytes and its cluster numbers in each hight power field of vision showed statistically significant decreament in CALR group as compared with JAK2 group (P=0.001, P=0.001), and thrombotic events in CALR group were signicantly lower than those in JAK2 group (7.5% vs 18.4%) (P=0.03). CONCLUSION: Mutations of CALR, JAK2 have different clinical characteristics and blood pathological changes of Chinese ET patients, and their clinical significance is worth to explore.


Assuntos
Trombocitemia Essencial , Medula Óssea , Calreticulina/genética , China , Humanos , Janus Quinase 2/genética , Masculino , Mutação , Receptores de Trombopoetina/genética
4.
Mol Cell ; 78(6): 1207-1223.e8, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32504554

RESUMO

Tumor interferon (IFN) signaling promotes PD-L1 expression to suppress T cell-mediated immunosurveillance. We identify the IFN-stimulated non-coding RNA 1 (INCR1) as a long noncoding RNA (lncRNA) transcribed from the PD-L1 locus and show that INCR1 controls IFNγ signaling in multiple tumor types. Silencing INCR1 decreases the expression of PD-L1, JAK2, and several other IFNγ-stimulated genes. INCR1 knockdown sensitizes tumor cells to cytotoxic T cell-mediated killing, improving CAR T cell therapy. We discover that PD-L1 and JAK2 transcripts are negatively regulated by binding to HNRNPH1, a nuclear ribonucleoprotein. The primary transcript of INCR1 binds HNRNPH1 to block its inhibitory effects on the neighboring genes PD-L1 and JAK2, enabling their expression. These findings introduce a mechanism of tumor IFNγ signaling regulation mediated by the lncRNA INCR1 and suggest a therapeutic target for cancer immunotherapy.


Assuntos
Antígeno B7-H1/genética , Interferon gama/metabolismo , RNA Longo não Codificante/genética , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia , Imunoterapia Adotiva/métodos , Interferon gama/genética , Interferons/genética , Interferons/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Citotóxicos
5.
Proc Natl Acad Sci U S A ; 117(26): 15047-15054, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32532922

RESUMO

Tamoxifen, a widely used modulator of the estrogen receptor (ER), targets ER-positive breast cancer preferentially. We used a powerful validation-based insertion mutagenesis method to find that expression of a dominant-negative, truncated form of the histone deacetylase ZIP led to resistance to tamoxifen. Consistently, increased expression of full-length ZIP gives the opposite phenotype, inhibiting the expression of genes whose products mediate resistance. An important example is JAK2 By binding to two specific sequences in the promoter, ZIP suppresses JAK2 expression. Increased expression and activation of JAK2 when ZIP is inhibited lead to increased STAT3 phosphorylation and increased resistance to tamoxifen, both in cell culture experiments and in a mouse xenograft model. Furthermore, data from human tumors are consistent with the conclusion that decreased expression of ZIP leads to resistance to tamoxifen in ER-positive breast cancer.


Assuntos
Neoplasias da Mama/enzimologia , Proteínas Quinases Associadas com Morte Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Tamoxifeno/farmacologia , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proteínas Quinases Associadas com Morte Celular/genética , Feminino , Humanos , Janus Quinase 2/genética , Camundongos , Camundongos SCID , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Fator de Transcrição STAT3/genética
6.
Leukemia ; 34(7): 1805-1815, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32518419

RESUMO

A subgroup of patients with severe COVID-19 suffers from progression to acute respiratory distress syndrome and multiorgan failure. These patients present with progressive hyperinflammation governed by proinflammatory cytokines. An interdisciplinary COVID-19 work flow was established to detect patients with imminent or full blown hyperinflammation. Using a newly developed COVID-19 Inflammation Score (CIS), patients were prospectively stratified for targeted inhibition of cytokine signalling by the Janus Kinase 1/2 inhibitor ruxolitinib (Rux). Patients were treated with efficacy/toxicity guided step up dosing up to 14 days. Retrospective analysis of CIS reduction and clinical outcome was performed. Out of 105 patients treated between March 30th and April 15th, 2020, 14 patients with a CIS ≥ 10 out of 16 points received Rux over a median of 9 days with a median cumulative dose of 135 mg. A total of 12/14 patients achieved significant reduction of CIS by ≥25% on day 7 with sustained clinical improvement in 11/14 patients without short term red flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation is shown to be safe with signals of efficacy in this pilot case series for CRS-intervention to prevent or overcome multiorgan failure. A multicenter phase-II clinical trial has been initiated (NCT04338958).


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Ensaios Clínicos como Assunto , Infecções por Coronavirus/enzimologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/enzimologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Esquema de Medicação , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Pneumonia Viral/enzimologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Síndrome Respiratória Aguda Grave/enzimologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia , Resultado do Tratamento
7.
PLoS One ; 15(6): e0232801, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32479500

RESUMO

The myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis are hematopoietic stem cell disorders and share driver mutations that either directly activate the thrombopoietin receptor, MPL, or activate it indirectly through gain-of-function mutations in the gene for JAK2, its cognate tyrosine kinase. Paradoxically, MPL surface expression in hematopoietic stem cells is also reduced in the myeloproliferative neoplasms due to abnormal post-translational glycosylation and premature destruction of JAK2, suggesting that the myeloproliferative neoplasms are disorders of MPL processing since MPL is the only hematopoietic growth factor receptor in hematopoietic stem cells. To examine this possibility, we genetically manipulated MPL expression and maturation in a JAK2V617F transgenic mouse model of polycythemia vera. Elimination of MPL expression completely abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could only be partially restored by expression of one MPL allele. Most importantly, elimination of thrombopoietin gene expression abrogated the polycythemia vera phenotype in this JAK2V617F transgenic mouse model, which could be completely restored by expression of a single thrombopoietin allele. These data indicate that polycythemia vera is in part a thrombopoietin-dependent disorder and that targeting the MPL-thrombopoietin axis could be an effective, nonmyelotoxic therapeutic strategy in this disorder.


Assuntos
Janus Quinase 2/genética , Policitemia Vera/genética , Policitemia Vera/metabolismo , Trombopoetina/genética , Trombopoetina/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Janus Quinase 2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Transtornos Mieloproliferativos/genética , Fenótipo , Policitemia Vera/patologia , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética
8.
Clin Immunol ; 218: 108517, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32585295

RESUMO

Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Síndrome Respiratória Aguda Grave/prevenção & controle , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Betacoronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/genética , Citocinas/imunologia , Cálculos da Dosagem de Medicamento , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/genética , Janus Quinase 1/imunologia , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/farmacocinética , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos
10.
Proc Natl Acad Sci U S A ; 117(24): 13670-13679, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32471953

RESUMO

Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Inibidores Enzimáticos/administração & dosagem , Histona Desmetilases/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores de Fator Estimulador de Colônias/genética , Fatores de Transcrição STAT/metabolismo , Animais , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Feminino , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Fator Estimulador de Colônias/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Transdução de Sinais/efeitos dos fármacos
11.
Ann Hematol ; 99(5): 983-989, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32277273

RESUMO

Molecular detection of JAK2 mutation (V617F or exon 12) is included as a major diagnostic criterion for polycythemia vera (PV) by the WHO 2016 guidelines. JAK2 exon 12 mutations are seen in about 2-5% of JAK2V617F-negative cases of PV. Mutations in JAK2 cause constitutive activation of JAK-STAT pathway which results in variable phenotypes. PV patients with exon 12 mutations in JAK2 present characteristically with erythrocytosis. There are limited reports describing the spectrum of JAK2 exon12 mutations in myeloproliferative neoplasms (MPNs). Here, we describe the characteristics of a series of MPN patients with mutations in exon 12 of JAK2 of which two were novel variants associated with polycythemia. Interestingly, we noted two patients presenting as myelofibrosis having JAK2 exon 12 mutations.


Assuntos
Éxons , Janus Quinase 2/genética , Mutação de Sentido Incorreto , Policitemia Vera/genética , Mielofibrose Primária/genética , Adulto , Substituição de Aminoácidos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Mol Carcinog ; 59(5): 503-511, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32133692

RESUMO

Lung adenocarcinoma (LUAD), as a form of non-small cell lung cancer (NSCLC), is the most frequently diagnosed lung cancer worldwide. To date, a few biomarkers have been reported to provide valuable information in guiding LUAD treatment. The aim of our study was to explore the functional role of pyrroline-5-carboxylate reductase 1 (PYCR1) in LUAD. Based on Oncomine database, we found that PYCR1 was highly expressed in LUAD tissues. We also confirmed an abnormal increase of PYCR1 expression in LUAD cell lines and patients' tissues. Through Kaplan-Meier plotter database, we further studied the prognostic values of PYCR1. The outcomes indicated that overexpressed PYCR1 associated with poor prognosis among LUAD patients. To further study the function of PYCR1 in LUAD, cell counting kit-8, colony-forming, scratch wound healing, and Transwell assays were conducted. The results suggested that knockdown of PYCR1 curbed cell proliferation, migration, and invasion in LUAD cell lines. Subsequently, we identified 50 top genes positively and negatively correlated with PYCR1 in LUAD, and conducted biological pathway enrichment analysis of these genes. Among those enriched pathways, we selected JAK/STAT signaling pathway for further analysis. The results of Western blot assays revealed that PYCR1 knockdown significantly increased the expression of Bcl-2 and c-Myc, and the phosphorylation level of JAK2 and STAT3. Taken together, this study unearthed that PYCR1 knockdown could inhibit tumor growth and affect the JAK/STAT signaling pathway in LUAD. This study may contribute to a better understanding of PYCR1 in LUAD and provide a potential biomarker for cancer prognosis.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Janus Quinase 2/metabolismo , Pirrolina Carboxilato Redutases/metabolismo , Fator de Transcrição STAT3/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/secundário , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Pirrolina Carboxilato Redutases/genética , Fator de Transcrição STAT3/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
14.
Pediatr Blood Cancer ; 67(5): e28183, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32124556

RESUMO

BACKGROUND: Essential thrombocythemia (ET) is rare in children, and pediatric guidelines are lacking. Therefore, we aimed to evaluate ET diagnosis and treatment in a pediatric cohort. PROCEDURE: Data of patients with ET from three hospitals were reviewed. Molecular diagnosis included JAK2V617F, CALR, and MPL mutations. Patients were evaluated for acquired von Willebrand syndrome (AVWS). Follow-up included clinical symptoms, adverse events, and treatment. RESULTS: Twelve children (median age: 8 years, range 1-14.5) were included. Mean lag period between the first documentation of thrombocytosis until ET diagnosis was 36 months. Six patients were positive for JAK2V617F and two for CALR mutations. In six of nine patients, AVWS was diagnosed. At diagnosis, only 33% of patients started therapy with aspirin (n = 4) and hydroxyurea (n = 2). In three of eight untreated patients, therapy was added during follow-up. The cohort was followed for a median of 32.5 months (range: 4-108 months). Clinical follow-up disclosed vascular complications in 4 of 12 patients (deep vein thrombosis, n = 1; transient ischemic attack, n = 3). Two females experienced excessive bleeding; both were diagnosed with AVWS. Neither leukemia nor myelofibrosis evolved in our cohort. CONCLUSION: Increased awareness to pediatric ET is warranted, as delayed diagnosis is common. Compared to adults, AVWS may be more prevalent among children with ET.


Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Mutação , Receptores de Trombopoetina/genética , Trombocitemia Essencial/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Trombocitemia Essencial/terapia
15.
Pediatr Blood Cancer ; 67(5): e28232, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32134181

RESUMO

OBJECTIVES: Pediatric myelofibrosis is a rare entity with the largest reported series of 19 cases. We describe here the clinicopathological spectrum and outcomes of 15 cases of pediatric myelofibrosis. METHODS: Case files of myelofibrosis of patients less than 18 years were retrieved from January 2016 to January 2019, and patients with idiopathic myelofibrosis after exhaustive work-up were studied. Their clinicopathological profiles were studied and then followed up for resolution and malignant transformation. RESULTS: Of the 15 cases of idiopathic myelofibrosis, transfusion-dependent anemia (14/15) was most common presentation. Only one patient showed leukoerythroblastosis with dacryocytes. Myeloid hyperplasia was seen in 13 of 15 patients and megakaryocytic hyperplasia in 10 patients. Dysmegakaryopoiesis was seen in 8 of 15 patients, and only three had small loose megakaryocytic clustering. None showed hyperchromatic megakaryocytes, intrasinusoidal hematopoiesis, or osteosclerosis. One patient with trisomy 8 tested positive for JAK2V617F. Bone marrow biopsy was hypercellular in 13, and 8 had world health organization (WHO) MF-3 fibrosis. None of the patients developed malignancy, one had spontaneous resolution, and one patient required allogenic stem cell transplant. CONCLUSIONS: Pediatric myelofibrosis is a distinct entity from primary myelofibrosis in adults and merits mention in the WHO manual as a distinct entity.


Assuntos
Transformação Celular Neoplásica , Janus Quinase 2 , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Trombopoese , Adolescente , Adulto , Substituição de Aminoácidos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Megacariócitos/metabolismo , Megacariócitos/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Osteosclerose/genética , Osteosclerose/metabolismo , Osteosclerose/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Estudos Retrospectivos
16.
PLoS One ; 15(2): e0228362, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017785

RESUMO

The histone demethylase JMJD1C is overexpressed in patients with myeloproliferative neoplasms (MPNs) and has been implicated in leukemic stem cell function of MLL-AF9 and HOXA9-driven leukemia. In the emerging field of histone demethylase inhibitors, JMJD1C therefore became a potential target. Depletion of Jmjd1c expression significantly reduced cytokine-independent growth in an MPN cell line, indicating a role for JMJD1C in MPN disease maintenance. Here, we investigated a potential role for the demethylase in MPN disease initiation. We introduced a Cre-inducible JAK2V617F mutation into Jmjd1c knockout mice. We show that Jmjd1c is dispensable, both for healthy hematopoiesis as well as for JAK2V617F-driven MPN disease initiation. Jmjd1c knockout mice did not show any significant changes in peripheral blood composition. Likewise, introduction of JAK2V617F into Jmjd1c-/- mice led to a similar MPN phenotype as JAK2V617F in a Jmjd1c wt background. This indicates that there is a difference between the role of JMJD1C in leukemic stem cells and in MPN. In the latter, JMJC domain-containing family members may serve redundant roles, compensating for the loss of individual proteins.


Assuntos
Hematopoese , Janus Quinase 2/genética , Histona Desmetilases com o Domínio Jumonji/genética , Mutação , Transtornos Mieloproliferativos/genética , Animais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Desenvolvimento Embrionário , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Camundongos Knockout
17.
Science ; 367(6478): 643-652, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029621

RESUMO

Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.


Assuntos
Carcinogênese/genética , Membrana Celular/química , Janus Quinase 2/química , Janus Quinase 2/genética , Multimerização Proteica , Receptores da Eritropoetina/química , Receptores da Somatotropina/química , Receptores de Trombopoetina/química , Substituição de Aminoácidos/genética , Células HeLa , Humanos , Janus Quinase 2/antagonistas & inibidores , Ligantes , Microscopia de Fluorescência , Modelos Moleculares , Mutação , Fenilalanina/genética , Pirazóis/farmacologia , Transdução de Sinais , Imagem Individual de Molécula , Valina/genética
20.
J Exp Clin Cancer Res ; 39(1): 9, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31928530

RESUMO

BACKGROUND: Localized C3 deposition is a well-known factor of inflammation. However, its role in oncoprogression of gastric cancer (GC) remains obscured. This study aims to explore the prognostic value of C3 deposition and to elucidate the mechanism of C3-related oncoprogression for GC. METHODS: From August to December 2013, 106 GC patients were prospectively included. The regional expression of C3 and other effectors in gastric tissues were detected by WB, IHC, qRT-PCR and other tests. The correlation of localized C3 deposition and oncologic outcomes was determined by 5-year survival significance. Human GC and normal epithelial cell lines were employed to detect a relationship between C3 and STAT3 signaling pathway in vitro experiments. RESULTS: C3 and C3a expression were markedly enhanced in GC tissues at both mRNA and protein levels compared with those in paired nontumorous tissues. According to IHC C3 score, 65 (61.3%) and 41 (38.7%) patients had high and low C3 deposition, respectively. C3 deposition was negatively correlated with plasma levels of C3 and C3a (both P < 0.001) and positively correlated with pathological T and TNM stages (both P < 0.001). High C3 deposition was identified as an independent prognostic factor of poor 5-year overall survival (P = 0.045). In vitro C3 administration remarkably enhanced p-JAK2/p-STAT3 expression in GC cell lines but caused a reduction of such activation when pre-incubated with a C3 blocker. Importantly, C3 failed to activate such signaling in cells pre-treated with a JAK2 inhibitor. CONCLUSIONS: Localized C3 deposition in the tumor microenvironment is a relevant immune signature for predicting prognosis of GC. It may aberrantly activate JAK2/STAT3 pathway allowing oncoprogression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02425930, Registered 1st August 2013.


Assuntos
Complemento C3/genética , Complemento C3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/patologia , Regulação para Cima , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Microambiente Tumoral
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