RESUMO
In this study, we investigated the role of inositol polyphosphate-4-phosphatase, type-II (INPP4B) in acute myeloid leukemia (AML). We observed that AML patients with high levels of INPP4B (INPP4B(high)) had poor response to induction therapy, shorter event-free survival and shorter overall survival. Multivariate analyses demonstrated that INPP4B(high) was an independent predictor of poor prognosis, significantly improving current predictive models, where it outperformed conventional biomarkers including FLT3-ITD and NPM1. Furthermore, INPP4B(high) effectively segregated relative risk in AML patients with normal cytogenetics. The role of INPP4B on the biology of leukemic cells was assessed in vitro. Overexpression of INPP4B in AML cell lines enhanced colony formation potential, recapitulated the chemotherapy resistance observed in AML patients and promoted proliferation in a phosphatase-dependent, and Akt-independent manner. These findings reveal that INPP4B(high) has an unexpected role consistent with oncogenesis in AML, in contrast to its previously reported tumor-suppressive role in epithelial cancers. Overall, we propose that INPP4B is a novel prognostic biomarker in AML that has potential to be translated into clinical practice both as a disease marker and therapeutic target.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Monoéster Fosfórico Hidrolases/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Western Blotting , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Quimiorradioterapia , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Imunofluorescência , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias , Nucleofosmina , Monoéster Fosfórico Hidrolases/genética , Prognóstico , RNA Mensageiro/genética , Radiação Ionizante , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Sequências de Repetição em Tandem/genética , Células Tumorais Cultivadas , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
The study evaluates three enzyme-linked immunosorbent assays (ELISA) of malaria antigens suitable for use in large-scale epidemiological studies. Results obtained using sera from 567 persons from the Gambia indicated that the micro-ELISA method using parasitized red blood cell extract did not reliably quantitate antimalarial antibodies, especially in young children. In contrast, two micro-ELISA methods that employed purified, defined antigens (a polypeptide of M(r) = 41 000 present in rhoptries, and a 31-1 fusion polypeptide corresponding to a merozoite surface antigen) permitted the precise determination of antimalarial antibodies in both adults and children. Problems and advantages associated with the use of the M(r) = 41 000 and 31-1 antigens for the determination of antimalarial antibodies are discussed.
Assuntos
Antígenos de Protozoários/imunologia , Malária/imunologia , Plasmodium falciparum/imunologia , Proteínas de Transporte/imunologia , Ensaio de Imunoadsorção Enzimática , HumanosRESUMO
Saimiri monkeys immunized with a Plasmodium falciparum merozoite polypeptide of 41 kD mol wt are resistant to a blood challenge infection that induces a fulminant infection in control monkeys. The sera of the immunized monkeys reacted, as shown by the indirect immunofluorescence technique, with the apical part of the merozoites from five isolates or clones of P. falciparum. Whether the immunogen was dissolved in nonionic detergent (NP-40) or in sodium dodecyl sulfate (SDS) had a marked influence on the level of protection in immunized monkeys. Thus, monkeys immunized with the antigen solubilized in a nonionic detergent developed much lower parasitemia than monkeys immunized with denatured antigen (antigen eluted from SDS polyacrylamide gel electrophoresis).