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1.
Haematologica ; 105(8): 2118-2129, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31649131

RESUMO

Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycolysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glutamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expression of asparagine synthetase (ASNS) and L-asp-induced suppression of glutamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L-asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.


Assuntos
Leucemia Mieloide Aguda , Proto-Oncogenes , Adulto , Asparaginase , Proteínas de Ligação a DNA/genética , Humanos , Leucemia Mieloide Aguda/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Proto-Oncogenes/genética , Fatores de Transcrição/genética
2.
Cancer Med ; 8(18): 7809-7821, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31692287

RESUMO

The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor-specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin-like growth factor-I receptor (IGF-IR), while PF-562,271 is a dual inhibitor of FAK and proline-rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF-562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF-562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF-IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.


Assuntos
Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Morfolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Sarcoma de Ewing/metabolismo , Animais , Apoptose/efeitos dos fármacos , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estadiamento de Neoplasias , Fosforilação , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Rinsho Ketsueki ; 60(5): 378-381, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31167998

RESUMO

Here, we report the case of a 9-year-old girl with acute myeloid leukemia (AML) developed from systemic mastocytosis (SM). She experienced bladder and rectal disturbance due to an extramedullary nodule in the paraspinal region of the sacrum. Cytogenetic and genetic analyses of leukemic cells revealed the KIT D816Y mutation besides t (8;21) (q22:q22) /RUNX1-RUNX1T1. Despite receiving proton beam therapy after conventional chemotherapy, the patient relapsed after 2 months. As SM-AML with the KIT D816 mutation in adults exhibits a poor prognosis, hematopoietic stem cell transplantation is recommended. Owing to a few reports of SM-AML in children, the standard therapy for pediatric cases has not been established to date. Based on our experience and the related literature, the prognosis of childhood SM-AML could be as poor as in adults. Hence, further investigation, including mutational analyses of the KIT gene, is warranted to establish a risk-oriented strategy for managing childhood SM-AML.


Assuntos
Leucemia Mieloide Aguda/complicações , Mastocitose Sistêmica/complicações , Criança , Feminino , Humanos , Mastocitose Sistêmica/tratamento farmacológico , Mutação , Prognóstico , Recidiva , Translocação Genética
4.
J Pediatr Hematol Oncol ; 41(6): e402-e404, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30044348

RESUMO

Systemic mastocytosis (SM) is a disorder characterized by abnormal proliferation of mast cells with KIT mutations, especially in codon 816. The prognosis of patients developing acute myeloid leukemia (AML) from SM is extremely poor, and hematopoietic cell transplantation is recommended. Herein, we describe a case of an 8-year-old female diagnosed with SM developing AML. A KIT M541L variant in SM was identified in leukemic cells, normal hematopoietic cells, and buccal mucosal cells, suggesting a germline polymorphism. The patient has remained in complete remission for 39 months after completion of chemotherapy. SM developing AML without a KIT D816 mutation may be not necessarily associated with a poor prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mastocitose Sistêmica/complicações , Criança , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/patologia , Prognóstico , Indução de Remissão
5.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28834127

RESUMO

A 3-year-old male presented with a large retroperitoneal mass and multiple metastases. Biopsy results suggested alveolar rhabdomyosarcoma bearing a methylated O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Serum microRNA-206 levels were elevated and remained high after three cycles of vincristine, dactinomycin, and cyclophosphamide (VAC). Replacement of vincristine, irinotecan, and temozolomide (VIT) for VAC induced a marked tumor reduction and normalization of the miR-206 levels. The patient completed 14 cycles of VIT with local radiotherapy and has been in remission for 31 months. Temozolomide could be effective for tumors with a methylated MGMT gene promoter. Individualized therapy is warranted for such patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , DNA de Neoplasias/metabolismo , Regiões Promotoras Genéticas , Rabdomiossarcoma Alveolar , Proteínas Supressoras de Tumor/metabolismo , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Pré-Escolar , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Dactinomicina/administração & dosagem , Humanos , Irinotecano , Masculino , MicroRNAs/metabolismo , Metástase Neoplásica , RNA Neoplásico/metabolismo , Rabdomiossarcoma Alveolar/metabolismo , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Alveolar/terapia , Temozolomida , Vincristina/administração & dosagem
6.
Pediatr Int ; 58(9): 905-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27460485

RESUMO

Inversion of chromosome 16 [inv(16)] has a good prognosis in acute myeloid leukemia (AML), but additional genetic aberrations influence the outcome. We herein describe the case of a 15-year-old Japanese boy with inv(16) harboring a low-allelic burden internal tandem duplication of FLT3 (FLT3-ITD) and KIT mutations. Conventional chemotherapy eradicated a clone with a low-allelic burden FLT3-ITD mutation, although another clone with a KIT mutation occurred 17 months later. Further investigation is necessary to identify AML with inv(16) conferring poor prognosis, to facilitate appropriate treatment with additional drugs, such as dasatinib or gemtuzumab ozogamicin.


Assuntos
Cromossomos Humanos Par 16/genética , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , RNA Mensageiro/genética , Adolescente , Alelos , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Prognóstico , Sequências de Repetição em Tandem
7.
Rinsho Ketsueki ; 54(3): 273-8, 2013 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-23676642

RESUMO

This report describes two infants with recurrent pulmonary edema after umbilical cord blood transplantation (CBT). A 3-month-old boy and a 7-month-old boy with infant acute lymphoblastic leukemia underwent CBT from an unrelated donor in the first complete remission. The conditioning regimen consisted of busulfan, etoposide, and cyclophosphamide. Tacrolimus and short-term methotrexate were administered for the prophylaxis of acute graft-versus-host disease (GVHD). Neutrophil engraftment was achieved on days 17 and 19, respectively. Neither infant developed acute GVHD. They both exhibited tachypnea and weight gain on days 25 and 30, respectively, which were diagnosed as pulmonary edema by chest X rays. The respiratory condition of the patients improved within a few days with the close monitoring of weight changes after the administration of diuretics. However, they suddenly developed dyspnea and pulmonary edema again on days 37 and 59, respectively. Steroid therapy was initiated for both patients. Their respiratory condition again improved quickly after the initiation of steroid therapy. Their symptoms and clinical courses may be classified as a new entity of idiopathic pneumonia syndrome (IPS). Therefore, these cases may represent a new unclassifiable IPS associated with either CBT or infants.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Edema Pulmonar/etiologia , Humanos , Lactente , Masculino , Edema Pulmonar/tratamento farmacológico , Recidiva , Resultado do Tratamento
8.
Rinsho Ketsueki ; 54(4): 383-7, 2013 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-23666221

RESUMO

We here report a 2-year-old female with relapsed acute myeloid leukemia (AML) with MLL gene rearrangement in the bone marrow and central nervous system. The 3'-RACE (Rapid Amplification of cDNA Ends) method identified the MLLT10 gene as a fusion partner of the MLL gene. The patient was complicated with hemophagocytic lymphohistiocytosis (HLH) and invasive aspergillosis (IPA) after re-induction treatment with FLAG-IDA following etoposide, cytarabine, and mitoxantrone. Although treatment with systemic anti-fungal drugs was effective for IPA, HLH did not improve. We considered tumor-associated HLH to be initiated from leukemic stem cells (LSCs) in the bone marrow niche because reverse transcription-polymerase chain reaction (RT-PCR) analysis of a bone marrow biopsy sample was positive for MLL-MLLT10. Gemtuzumab ozogamicin and sorafenib had no major effect on acquiring complete remission, and the patient died of progressive AML with an exacerbation of HLH and aspergillosis. LSCs are known to be resistant to conventional chemotherapy due to their quiescence in the cell cycle. Novel therapeutic concepts are important to eradicate LSCs in order to cure AML patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções Fúngicas do Sistema Nervoso Central/terapia , Leucemia Mieloide Aguda/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Infecções Fúngicas do Sistema Nervoso Central/complicações , Pré-Escolar , Citarabina/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/imunologia , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/imunologia , Mitoxantrona/administração & dosagem
9.
Pediatr Blood Cancer ; 60(1): 116-20, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22847790

RESUMO

BACKGROUND: For children with juvenile myelomonocytic leukemia (JMML) who undergo stem cell transplantation (SCT), the role of immunological interventions including withdrawal of immunosuppressive therapy (IST) and donor lymphocyte infusion (DLI) for treatment of disease recurrence remains uncertain. PROCEDURE: We analyzed serial chimerism status following SCT and evaluated the efficacy of immunological interventions for the management of mixed chimerism (MC) in children with JMML. RESULTS: Chimerism analysis was available in 26 SCT cases following the first and second SCT. MC was observed in 16 cases and withdrawal of IST was performed in 14 cases immediately after identification of MC. Donor lymphocyte infusion (DLI) was performed in five MC cases. Eight MC cases were observed at the time of neutrophil recovery. Following withdrawal of IST, three cases achieved complete chimerism (CC) while the proportion of autologous cells increased rapidly in the remaining five cases. Six MC cases were observed after achievement of hematological remission (HR) and responses to withdrawal of IST were observed in two cases. In the remaining four cases, despite withdrawal of IST, the proportion of autologous cells increased. Five cases received DLI but only one case responded. CONCLUSION: Although the benefits of immunological interventions for MC after SCT in JMML were limited, some patients did achieve HR as a result of these treatment modalities without a second SCT. Close monitoring of donor chimerism and early detection of MC is helpful in guiding treatment after SCT in children with JMML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil/terapia , Pré-Escolar , Quimerismo , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/imunologia , Transfusão de Linfócitos , Masculino , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento
10.
Pediatr Transplant ; 16(7): 722-8, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22694185

RESUMO

The impact of a second all-SCT on the long-term outcomes of children who relapse after allo-SCT has been unclear. We retrospectively analyzed the long-term outcomes of different salvage treatments for such children. Sixty-six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo-SCT received either a second allo-SCT (n = 16) or CTx and/or DLI (n = 50). The median follow-up for all children was 9.1 yr. The five-yr OS after relapse was significantly better in patients who underwent a second allo-SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight-yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo-SCT, two died more than five yr after the second allo-SCT. A second allo-SCT can therefore lead to a prolonged OS in patients who relapse after allo-SCT. However, a second allo-SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo-SCT.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
11.
Am J Hematol ; 87(4): 447-50, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22389016
12.
Brain Tumor Pathol ; 29(2): 107-12, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22139530

RESUMO

Congenital malignant gliomas are rare brain tumors about which few reports have been published. We present the clinical course and genetic alterations in an infant with a congenital malignant glioma detected incidentally by ultrasonography at 36 weeks. The tumor occupied the right temporoparietal region, extended to the posterior fossa, and significantly compressed surrounding structures. The female infant was entirely normal without macrocrania, tense fontanel, or sucking difficulties. The tumor was subtotally resected by two-stage surgery; pathological diagnosis was anaplastic astrocytoma. Immunohistochemical staining was positive for p53 and negative for epidermal growth factor receptor. There was no O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation, no 1p/19q loss of heterozygosity, and no isocitrate dehydrogenase 1 (IDH1) mutation. She underwent postoperative chemotherapy and is alive and well 12 months after surgery.


Assuntos
Astrocitoma/congênito , Astrocitoma/genética , Neoplasias Encefálicas/congênito , Neoplasias Encefálicas/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Astrocitoma/terapia , Neoplasias Encefálicas/terapia , Carboplatina/administração & dosagem , Terapia Combinada , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Etoposídeo/administração & dosagem , Feminino , Humanos , Achados Incidentais , Recém-Nascido , Isocitrato Desidrogenase/genética , Procedimentos Neurocirúrgicos , Gravidez , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genética , Ultrassonografia Pré-Natal
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