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1.
Zhonghua Er Ke Za Zhi ; 57(10): 761-766, 2019 Oct 02.
Artigo em Chinês | MEDLINE | ID: mdl-31594062

RESUMO

Objective: To evaluate the efficacy of the Chinese Children's Leukemia Group (CCLG) acute lymphoblastic leukemia (ALL) 2008 protocol (CCLG-ALL 2008) in the treatment of children's T-cell acute lymphoblastic leukemia (T-ALL). Methods: Clinical characteristics and outcomes of 84 newly diagnosed T-ALL children (63 males and 21 females) treated with CCLG-ALL 2008 protocol from April 2008 to April 2015 in the Department of Pediatric Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences were analyzed retrospectively. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event free survival (EFS), and COX regression was used to evaluate the influencing factors of OS and EFS. Results: (1) Baseline data: 84 children were included, 56 cases (67%) of children were younger than 10 years old. Patients whose white blood cell count≥50×10(9)/L ranked 70% (59/84). Karyotype: 58% (49/84) with normal karyotype, 10% (8/84) with abnormality of chromosome 11, 8%(7/84) with abnormality of chromosome 9, 2%(2/84) with abnormality in both chromosome 11 and chromosome 9, 8% (7/84) with other complex karyotypes. Fusion gene: 33%(28/84) were SIL-TAL1 positive. The patients were grouped by CCLG-ALL 2008 risk score, 40% (34/84) were in the intermediate risk group and 60% (50/84) in the high risk group. (2) Treatment efficacy: 84 cases were followed up until May 30, 2018. The follow-up time was 42.0 (0.3-120.0) months. The sensitivity rate of prednisone treatment was 56% (47/84); the complete response (CR) rate after the induction therapy of vincristine+daunoblastina+L-asparaginase+dexamethasone (VDLD)(d 33) was 88% (74/84); the total CR rate after VDLD induction combined with cyclophosphamide+cytarabine+6-mercaptopurine (CAM) treatment (d80) was 94% (79/84); the recurrence rate was 24% (20/84). Among the 20 recurrent cases, there were 13 cases (65%) with ultra-early recurrence (within 18 months after diagnosis), 6 cases (30%) with early recurrence (18 to 36 months after diagnosis); 1 patient (5%) with late recurrence (over 36 months after diagnosis). During the follow-up period, twenty-eight children (33%) died (22 cases with recurrence or suspending treatment without remission, 2 cases with infection, 1 case of sudden death in chemotherapy, 1 patient failed in transplantation, 1 patient with severe cirrhosis, and 1 patient with unknown cause). (3) Kaplan-Meier analysis: the 5-year OS and EFS of the 84 children were (63±6)% and (60±6)% respectively. (4) Efficacy in different risk groups: prednisone sensitivity rates in the two different risk groups were 100% (34/34) and 26% (13/50), respectively (χ(2)=3.237, P<0.05). The CR rates at the end of VDLD induction therapy (d 33) were 100% (34/34) and 80% (40/50), respectively (χ(2)=2.767, P<0.05). The recurrence rate of children in the two groups was 12% (4/34) and 32% (16/50), respectively (χ(2)=4.245, P<0.05).The mortality rates of the two groups were 21% (7/34) and 42% (21/50), respectively (χ(2)=3.198, P<0.05). Kaplan-Meier analysis showed that the 5-year OS of the two groups were (77±7)% and (53±8)%; and the 5-year EFS of the two groups were (75±8)% and (49±8)% (χ(2)=4.235, 3.875, both P<0.05) . (5) COX multivariate regression analysis showed that the classification of risk according to CCLG-ALL 2008 was an important factor influencing the prognosis of children with T-ALL (OR=3.313, 95% CI 1.165-9.422, P=0.025). Conclusions: The results of the risk group treatment according to the CCLG-ALL 2008 protocol showed that the long-term survival of children with middle risk was significantly better than that of children at high risk.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Criança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
2.
Zhonghua Yi Xue Za Zhi ; 99(36): 2820-2825, 2019 Sep 24.
Artigo em Chinês | MEDLINE | ID: mdl-31550809

RESUMO

Objective: To investigate the genetic characteristics and clinical outcomes of pediatric acute myeloid leukemia patients with NUP98-NSD1 fusion gene. Methods: A total of 80 pediatric AML patients were enrolled in this study, and bone marrow specimens were collected at initial diagnosis and relapse. NUP98-NSD1 was screened by fluorescence in situ hybridization (FISH) and PCR. Other laboratory test results and clinical outcomes were further analyzed for the NUP98-NSD1 positive cases. Results: A total of eight patients (10.0%) were positive for NUP98-NSD1, which were all fusions of NUP98 exon12 and NSD1 exon 6. There were two M2, three M4, and three M5 cases according to the French-American-British classification. Seven patients had karyotype results at the time of initial diagnosis, and none of them had complicated karyotype abnormalities. Among these patients, two cases had normal karyotype, three cases had trisomy 8, one case had trisomy 6, and two cases had anomalies involving 9q13 or 9q21. Additional karyotypic abnormalities and clonal evolutions were observed during disease progression or relapse, five cases had 9q13 or 9q32 abnormalities. Five cases (62.5%) were positive with FLT3-ITD mutation. Patients were treated with DAE/NAE/HAE/IA chemotherapy. Three cases did not achieve remission after several courses of chemotherapy, and five cases achieved remission but relapsed in 1 to 19 months. Five cases underwent salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among whom, four died in 40 days to 4 months after transplantation, and one survived 8.5 months till the last follow-up. Conclusions: NUP98-NSD1 is a recurrent genetic abnormality with significant clinical prognostic significance, and this group of disease has unique clinical and genetic characteristics. NUP98-NSD1 should be screened by FISH or PCR for children with AML who are newly diagnosed or refractory and relapsed to identify the high-risk genetic marker.


Assuntos
Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica/genética , Criança , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Mutação
3.
Genes Dev ; 33(17-18): 1265-1279, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31395741

RESUMO

Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL.


Assuntos
Regulação Leucêmica da Expressão Gênica , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Biomarcadores Tumorais/genética , Sobrevivência Celular/genética , Células Cultivadas , Deleção de Genes , Marcação de Genes , Humanos , Camundongos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico , Regiões Promotoras Genéticas/genética
4.
Expert Rev Clin Pharmacol ; 12(10): 931-939, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31469968

RESUMO

Introduction: Detecting oncogenic drivers across multiple cancers has brought about a shift toward a more targeted therapeutic approach. Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are genomic rearrangements containing the kinase domain of one of three tropomyosin receptor kinases (TRK) and a dimerization domain contributed by another gene, generating fusion proteins, which are oncogenic drivers, targetable with TRK inhibitors. Larotrectinib is a first-in-class TRK inhibitor, granted accelerated FDA approval for treating TRK fusion cancer. This breakthrough indication across cancer subtypes and ages, from infancy through adulthood, highlights the need to understand the heterogeneous patient population and cancer types studied in larotrectinib clinical trials. Areas covered: We provide a narrative review of preclinical, pharmacokinetic, efficacy, and safety data for larotrectinib from three clinical trials that led to regulatory approval. Expert opinion: Larotrectinib elicits impressive responses in most patients with TRK fusion cancer, regardless of tumor type and age. Treatment is well tolerated with a low rate of treatment-emergent grade 3-4 adverse events, dose reductions and discontinuations due to adverse events, and recent findings indicate patient-reported improvement in quality of life. This highlights the importance of early testing for NTRK gene fusions in cancers that may harbor them, even if rare.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Fusão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/efeitos adversos , Pirazóis/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética
6.
Cancer Sci ; 110(10): 3382-3390, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444835

RESUMO

Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non-small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK-rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next-generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4-ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R2  = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle-aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK-rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non-EML4-ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4-ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular-clinical profiles of patients with ALK-rearranged NSCLC that may improve the treatment strategy of this population.


Assuntos
Quinase do Linfoma Anaplásico/genética , Grupo com Ancestrais do Continente Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/genética , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Estudos Prospectivos , Análise de Sequência de DNA , Translocação Genética
7.
Nat Med ; 25(9): 1422-1427, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406350

RESUMO

TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Receptor trkA/genética , Adolescente , Adulto , Animais , Benzamidas/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ácidos Nucleicos Livres/efeitos dos fármacos , Ácidos Nucleicos Livres/genética , Criança , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Xenoenxertos , Humanos , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Pirimidinas/administração & dosagem , Pirimidinonas/administração & dosagem , Adulto Jovem
8.
Nat Commun ; 10(1): 3004, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285436

RESUMO

Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry are of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs to induce the expression of other CR TFs, providing a model system for studying cancer cell addiction to CR transcription. Using chemical genetics, the systematic screening of chemical matter for a biological outcome, here we report on a screen for epigenetic chemical probes able to distinguish between SE-driven transcription and constitutive transcription. We find that chemical probes along the acetylation-axis, and not the methylation-axis, selectively disrupt CR transcription. Additionally, we find that histone deacetylases (HDACs) are essential for CR TF transcription. We further dissect the contribution of HDAC isoforms using selective inhibitors, including the newly developed selective HDAC3 inhibitor LW3. We show HDAC1/2/3 are the co-essential isoforms that when co-inhibited halt CR transcription, making CR TF sites hyper-accessible and disrupting chromatin looping.


Assuntos
Elementos Facilitadores Genéticos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Rabdomiossarcoma/genética , Acetilação/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatina/efeitos dos fármacos , Cromatina/metabolismo , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Ensaios de Triagem em Larga Escala , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Humanos , Simulação de Dinâmica Molecular , Sondas Moleculares/química , Sondas Moleculares/farmacologia , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Cultura Primária de Células , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Rabdomiossarcoma/patologia , Análise de Sequência de RNA , Transcrição Genética/efeitos dos fármacos
9.
Ceska Gynekol ; 84(3): 212-215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324112

RESUMO

OBJECTIVE: Case description of advanced biphasic synovial sarcoma in the tubo-ovarian area. DESIGN: Case report. SETTING: Department of Pathology, Znojmo Hospital. METHODS: Own observation, review of the literature. CONCLUSION: The diagnosis of synovial sarcoma must be considered in all spindle cell and undifferentiated tumours in various anatomical sites including female reproductive organs.


Assuntos
Neoplasias das Tubas Uterinas/patologia , Neoplasias Ovarianas/patologia , Sarcoma Sinovial/patologia , Animais , Neoplasias das Tubas Uterinas/genética , Tubas Uterinas , Feminino , Humanos , Proteínas de Fusão Oncogênica/genética , Neoplasias Ovarianas/genética , Ovário , Sarcoma Sinovial/genética , Sarcoma Sinovial/cirurgia
10.
Ann Hematol ; 98(10): 2463-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240468
11.
Medicine (Baltimore) ; 98(24): e15912, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192927

RESUMO

RATIONALE: The differential diagnosis of conditions manifesting as bone and joint pain is complex. Although many individuals with acute leukemia experience bone pain, lumbosacral pain as an early feature of acute lymphoblastic leukemia (ALL) is rare. PATIENT CONCERNS: Here we report a case of an adult who presented with a 7-month history of persistent lumbosacral pain which had become more severe during the previous month. DIAGNOSES: Prior to referral, his full blood count revealed no abnormalities, and a computerized tomography scan revealed mild bone hyperplasia of his lumbar vertebrae, with disc herniations of L3-S1. His blood biochemistry and urinary test results had been normal. After referral to our clinic, tests of the morphology, immunology, cytogenetics, and molecular biology of his bone marrow led to a diagnosis of MLL-AF4 fusion positive B-cell ALL. INTERVENTIONS: Prior to his referral, he had been treated with painkillers by local doctors. The painkillers initially provided pain relief, but their effect wore off over time. After diagnosis, he was started on an adult ALL chemotherapy protocol. OUTCOMES: His symptoms resolved within a week of starting chemotherapy. At his most recent assessment, 10 months after diagnosis, he was on maintenance chemotherapy and in remission. LESSONS: This case illustrates that prolonged lumbosacral pain may be a symptom of a life-threatening condition, rather than only attributable to chronic inflammation or disk herniations. Therefore, clinicians need to pay attention to subtle differences in the clinical presentation of patients with lumbosacral pain.


Assuntos
Deslocamento do Disco Intervertebral/diagnóstico por imagem , Dor Lombar/etiologia , Região Lombossacral/diagnóstico por imagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adulto , Diagnóstico Diferencial , Tratamento Farmacológico , Humanos , Deslocamento do Disco Intervertebral/etiologia , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Resultado do Tratamento
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 637-640, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204910

RESUMO

OBJECTIVE: To explore the clinical features and therapeutic efficacy in adult ALL patients with t (1; 19) (E2A-PBX1). METHODS: The clinic data of 19 adult ALL patients with t (1; 19) (E2A-PBX1) in our hospital from Nov. 22, 2010 to Apr. 4, 2018 were collected. The clinical features,complete remission (CR) rate, overall survival (OS) rate and relapse-free survival (RFS) rate of patients received chemotherapy and chemotherapy+HSCT were analyzed. RESULTS: In all the 19 patients, the median age was 24 (14-66), median WBC count was 16.47×109 (1.8-170.34)/L, median Hb level was 98 (65-176) g/L, median Plt count was 50 (15-254)×109/L. Pre B-ALL were 17 cases (89.5%), and common B-ALL were 2 cases (10.5%). Patients received the induction therapy, the overall CR rate was 94.7%, one course CR rate was 94.7%, 4 year OS rate was 47.1% and RFS rate was 43.3%. The OS rate and RFS rate of patients received transplantation were slightly higher than those of patients not received transplantation (OS: 62.5% vs 36.7%) (P=0.188);RFS (62.5% vs 38.9%) (P=0.166). CONCLUSION: Most adult ALL patients with t (1; 19) (E2A-PBX1) is Pre B-ALL by Immunophenotyping, as compared with the pediatric patients, the therapeutic efficacy for adult patients with t (1; 19) (E2A-PBX1) is worsen, therefore, stem cell transplantation is still acquired for better long term survival.


Assuntos
Proteínas de Homeodomínio/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Humanos , Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Indução de Remissão
13.
Int J Mol Sci ; 20(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096545

RESUMO

Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.


Assuntos
Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Adolescente , Adulto , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Dineínas/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Humanos , Fator de Transcrição Ikaros/genética , Lactente , Masculino , México , Proteínas Nucleares/genética , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas de Ligação ao Cap de RNA/genética , Proteínas de Ligação a RNA/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Adulto Jovem
14.
Clin Cancer Res ; 25(15): 4674-4681, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31068372

RESUMO

PURPOSE: Gene fusions involving neuregulin 1 (NRG1) have been noted in multiple cancer types and have potential therapeutic implications. Although varying results have been reported in other cancer types, the efficacy of the HER-family kinase inhibitor afatinib in the treatment of NRG1 fusion-positive pancreatic ductal adenocarcinoma is not fully understood. EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving NRG1 received afatinib treatment, with response measured by pretreatment and posttreatment PET/CT imaging. RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as KRAS wild type by whole-genome sequencing. All KRAS wild-type tumors were positive for gene fusions involving the ERBB3 ligand NRG1. Two of 3 patients with NRG1 fusion-positive tumors were treated with afatinib and demonstrated a significant and rapid response while on therapy. CONCLUSIONS: This work adds to a growing body of evidence that NRG1 gene fusions are recurrent, therapeutically actionable genomic events in pancreatic cancers. Based on the clinical outcomes described here, patients with KRAS wild-type tumors harboring NRG1 gene fusions may benefit from treatment with afatinib.See related commentary by Aguirre, p. 4589.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pancreáticas , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Neuregulina-1 , Proteínas de Fusão Oncogênica/genética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Proteínas Proto-Oncogênicas p21(ras)
15.
Semin Oncol ; 46(2): 133-144, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31126665

RESUMO

Classical acute promyelocytic leukemia (APL) cases are associated with the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) chimeric fusion protein. Almost all the variant chimeric proteins share the same RARα component. Currently, more than 11 fusion partners of RARα have been identified, of which PML accounts for 95%, promyelocytic leukemia zinc finger (PLZF) take up2%, and the remaining are other variants. Although all-trans retinoic acid and arsenic trioxide have shown remarkable induction of molecular remission in classical APL, they have no appreciable effects on APL associated with other variant gene fusions (eg, PLZF-RARα and STAT5b-RARα). Here, we summarize all variant translocations, their key features, their leukemogenic potential as well as recent advances in studies of PLZF-RARα-associated APL. Basic pathogenic differences between classical APL and PLZF-RARα-associated APL are further discussed. We also highlight the critical leukemogenic events that are the backbone of these variant translocations so as to gain new insights into refractory APL.


Assuntos
Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Humanos , Leucemia Promielocítica Aguda/patologia , Leucemia Promielocítica Aguda/terapia , Fator de Transcrição STAT5/genética , Tretinoína/uso terapêutico
16.
Virchows Arch ; 475(4): 527-531, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31101969

RESUMO

Endometrial stromal sarcoma (ESS) is a rare mesenchymal neoplasm. Herein, we report a low-grade ESS with a novel MEAF6-SUZ12 fusion gene. A 40-year-old woman presented with a 9.0-cm abdominal wall mass juxtaposed to the postoperative scar of surgeries for uterine "leiomyomas" and cesarean section. Histologically, mostly hypocellular and myxoid nodules were comprised of uniform spindle cells and exhibited tongue-like infiltration. Immunohistochemically, the tumor cells were positive for CD10, estrogen receptor, and CD34 (focal). There were occasional h-caldesmon-positive cohesive nests. RNA sequencing along with reverse transcriptase-polymerase chain reaction and Sanger sequencing identified an in-frame fusion of MEAF6 (exon 4) and SUZ12 (exon 2). Upon review of the previous "leiomyomas," we revised their diagnoses as low-grade ESS. The patient is alive without disease 2 years after the surgery. In addition to expanding the molecular landscape of low-grade ESS, this case highlights the challenge of diagnosing low-grade ESS in an uncommon clinicopathological setting.


Assuntos
Neoplasias do Endométrio/genética , Proteínas de Fusão Oncogênica/genética , Complexo Repressor Polycomb 2/genética , Sarcoma do Estroma Endometrial/genética , Adulto , Neoplasias do Endométrio/patologia , Feminino , Humanos , Sarcoma do Estroma Endometrial/patologia
17.
Medicine (Baltimore) ; 98(19): e15537, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083206

RESUMO

RATIONALE: The vast majority of acute promyelocytic leukemia (APL) is characterized with a specific chromosomal translocation t (15, 17) (q22, q21), which fuses PML-RARα leading to a good response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, there are few cases of atypical APL, including PLZF-RARα, F1P1L1-RARα, STAT5b-RARα, et al. Neither PLZF-RARα nor STAT5b-RARα are sensitive to ATRA and ATO, and the prognosis is poor. PATIENT CONCERNS: Here we have 3 cases (PLZF-RARα, n = 2; STAT5b-RARα, n = 1). Case A, A 53-year-old Chinese female had suffered ecchymosis in both legs for 3 days. Case B, A 44 years old male suffered pain from lower limbs and hip. Case C, 52-year-old male patient presented with fever for 3 weeks invalid to antibiotics and gingival bleeding for 1 week. DIAGNOSES: With RT-PCR and karyotype, Case A is diagnosed with STAT5b-RARα-positive APL.Case B, C are diagnosed with PLZF-RARα-positive APL. INTERVENTIONS: In case A, ATO, and ATRA were used for induction treatment. In Case B, ATO, and chemotherapy with DA were given in the first induction treatment. In Case C, ATRA, and ATO were used immediately, subsequently, chemotherapy was added with DA, ATRA, and CAG combination treatment, and medium-dose cytarabine with daunorubicin were given regularly. OUTCOMES: In Case A, the patient refused the following treatment and discharged on day 25. In Case B, the patient got the disseminated intravascular coagulation (DIC).In Case C, the patient has survived for 7 months and remains CR. LESSONS: Both STAT5b-RARα-positive APL and PLZF-RARα-positive APL appear to be resistant to both ATRA and ATO, so combined chemotherapy and allo-HSCT should be considered. Since the prognosis and long-term outcome are poor, more clinical trials, and researches should be taken.


Assuntos
Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição STAT5/genética , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade
18.
J Clin Pathol ; 72(7): 460-467, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31072837

RESUMO

The neurotrophic tyrosine receptor kinase (NTRK) gene family encodes three tropomyosin receptor kinases (TRKA, TRKB, TRKC) that contribute to central and peripheral nervous system development and function. NTRK gene fusions are oncogenic drivers of various adult and paediatric tumours. Several methods have been used to detect NTRK gene fusions including immunohistochemistry, fluorescence in situ hybridisation, reverse transcriptase polymerase chain reaction, and DNA- or RNA-based next-generation sequencing. For patients with TRK fusion cancer, TRK inhibition is an important therapeutic target. Following the FDA approval of the selective TRK inhibitor, larotrectinib, as well as the ongoing development of multi-kinase inhibitors with activity in TRK fusion cancer, testing for NTRK gene fusions should become part of the standard diagnostic process. In this review we discuss the biology of NTRK gene fusions, and we present a testing algorithm to aid detection of these gene fusions in clinical practice and guide treatment decisions.


Assuntos
Neoplasias/genética , Fatores de Crescimento Neural/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/genética , Algoritmos , Humanos , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fatores de Crescimento Neural/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética
19.
Int J Mol Sci ; 20(9)2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083279

RESUMO

Fusion genes have been identified as oncogenes in several solid tumors including lung, colorectal, and stomach cancers. Here, we characterized the fusion gene, VAPA-Rab31, discovered from RNA-sequencing data of a patient with lung adenocarcinoma who did not harbor activating mutations in EGFR, KRAS and ALK. This fusion gene encodes a protein comprising the N-terminal region of vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) fused to the C-terminal region of Ras-related protein 31 (Rab31). Exogenous expression of VAPA-Rab31 in immortalized normal bronchial epithelial cells demonstrated the potential transforming effects of this fusion gene, including increased colony formation and cell proliferation in vitro. Also, enhanced tumorigenicity upon VAPA-Rab31 was confirmed in vivo using a mouse xenograft model. Metastatic tumors were also detected in the liver and lungs of xenografted mice. Overexpression of VAPA-Rab31 upregulated anti-apoptotic protein Bcl-2 and phosphorylated CREB both in cells and xenograft tumors. Reduced apoptosis and increased phosphorylation of CREB and Erk were observed in VAPA-Rab31-overexpressing cells after bortezomib treatment. Elevated Bcl-2 level via activated CREB contributed to the resistance to the bortezomib-induced apoptosis. Our data suggest the oncogenic function of the novel fusion gene VAPA-Rab31 via upregulated Bcl-2 and activated CREB in lung cancer.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Carcinogênese/genética , Carcinogênese/patologia , Proteínas de Fusão Oncogênica/genética , Sequência de Aminoácidos , Animais , Apoptose/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Nus , Proteínas de Fusão Oncogênica/química , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ensaio Tumoral de Célula-Tronco , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Sci ; 110(7): 2200-2210, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050834

RESUMO

Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c-Kit+ cells, LSCs). Importantly, we also observed that a higher level of Six1 in human patients predicts a worse prognosis. Notably, knockdown of Six1 significantly prolonged the survival of MLL-AF9-induced AML mice with reduced peripheral infiltration and tumor burden. AML cells from Six1-knockdown (KD) mice displayed a significantly decreased number and function of LSC, as assessed by the immunophenotype, colony-forming ability and limiting dilution assay. Further analysis revealed the augmented apoptosis of LSC and decreased expression of glycolytic genes in Six1 KD mice. Overall, our data showed that Six1 is essential for the progression of MLL-AF9-induced AML via maintaining the pool of LSC.


Assuntos
Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Regulação para Cima , Animais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Neoplasias Experimentais , Células-Tronco Neoplásicas/metabolismo , Prognóstico
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