NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2020-06-25

AUTHORS

Carolina Hassibe Thomé, Germano Aguiar Ferreira, Diego Antonio Pereira-Martins, Guilherme Augusto dos Santos, César Alexander Ortiz, Lucas Eduardo Botelho de Souza, Lays Martins Sobral, Cleide Lúcia Araújo Silva, Priscila Santos Scheucher, Cristiane Damas Gil, Andréia Machado Leopoldino, Douglas R. A. Silveira, Juan L. Coelho-Silva, Fabíola Traina, Luisa C. Koury, Raul A. M. Melo, Rosane Bittencourt, Katia Pagnano, Ricardo Pasquini, Elenaide C. Nunes, Evandro M. Fagundes, Ana Beatriz F. Gloria, Fábio Rodrigues Kerbauy, Maria de Lourdes Chauffaille, Armand Keating, Martin S. Tallman, Raul C. Ribeiro, Richard Dillon, Arnold Ganser, Bob Löwenberg, Peter Valk, Francesco Lo-Coco, Miguel A. Sanz, Nancy Berliner, Vitor Marcel Faça, Eduardo M. Rego

ABSTRACT

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17–11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment. More... »

PAGES

10315

References to SciGraph publications

Journal

TITLE

Scientific Reports

ISSUE

1

VOLUME

10

Author Affiliations

  • Regional Blood Center of Ribeirão Preto, Medical School of Ribeirão Preto, Center for Cell Based Therapy, University of São Paulo, Ribeirão Preto, Brazil
  • Department of Clinical Analyses, Toxicology and Food Sciences, University of São Paulo, Ribeirão Preto, Brazil
  • Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil
  • Hematology, Medical School, University of São Paulo, São Paulo, Brazil
  • Department of Internal Medicine, University of Pernambuco, Recife, Brazil
  • Hematology Division, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
  • Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil
  • Hematology Division, Federal University of Paraná, Curitiba, Brazil
  • Hematology Division, Federal University of Minas Gerais, Belo Horizonte, Brazil
  • Federal University of São Paulo, São Paulo, Brazil
  • Cell Therapy Program, Princess Margaret Cancer Centre, Toronto, Canada
  • Leukemia Service, Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College, New York, USA
  • Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
  • Department of Medical and Molecular Genetics, King’s College London School of Medicine, London, UK
  • Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
  • Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
  • Santa Lucia Foundation, Rome, Italy
  • CIBERONC, Instituto Carlos III, Madrid, Spain
  • Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
  • LIM31, Hematology, Medical School, University of São Paulo, São Paulo, Brazil
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41598-020-66223-2

    DOI

    http://dx.doi.org/10.1038/s41598-020-66223-2

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1128746282

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/32587277


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    42 schema:description Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17–11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
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