NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia
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...
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2020
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oai:doaj.org-article:1687378c1dd345e09a5c08f24c4834592021-12-02T17:45:12ZNTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia10.1038/s41598-020-66223-22045-2322https://doaj.org/article/1687378c1dd345e09a5c08f24c4834592020-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-66223-2https://doaj.org/toc/2045-2322Abstract 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.Carolina Hassibe ThoméGermano Aguiar FerreiraDiego Antonio Pereira-MartinsGuilherme Augusto dos SantosCésar Alexander OrtizLucas Eduardo Botelho de SouzaLays Martins SobralCleide Lúcia Araújo SilvaPriscila Santos ScheucherCristiane Damas GilAndréia Machado LeopoldinoDouglas R. A. SilveiraJuan L. Coelho-SilvaFabíola TrainaLuisa C. KouryRaul A. M. MeloRosane BittencourtKatia PagnanoRicardo PasquiniElenaide C. NunesEvandro M. FagundesAna Beatriz F. GloriaFábio Rodrigues KerbauyMaria de Lourdes ChauffailleArmand KeatingMartin S. TallmanRaul C. RibeiroRichard DillonArnold GanserBob LöwenbergPeter ValkFrancesco Lo-CocoMiguel A. SanzNancy BerlinerVitor Marcel FaçaEduardo M. RegoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020) |
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Medicine R Science Q 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 NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| description |
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. |
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article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Carolina Hassibe Thomé |
| title |
NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| title_short |
NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| title_full |
NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| title_fullStr |
NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| title_full_unstemmed |
NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| title_sort |
ntal is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia |
| publisher |
Nature Portfolio |
| publishDate |
2020 |
| url |
https://doaj.org/article/1687378c1dd345e09a5c08f24c483459 |
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