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

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

doi:10.1038/s41598-020-66223-2

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

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 NunesEvandro 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

Medical & Molecular Genetics

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6 Citations (Scopus)

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.

Original language	English
Article number	10315
Pages (from-to)	10315
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-66223-2
Publication status	Published - 25 Jun 2020

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10.1038/s41598-020-66223-2

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Thomé, C. H., Ferreira, G. A., Pereira-Martins, D. A., Dos Santos, G. A., Ortiz, C. A., de Souza, L. E. B., Sobral, L. M., Silva, C. L. A., Scheucher, P. S., Gil, C. D., Leopoldino, A. M., Silveira, D. R. A., Coelho-Silva, J. L., Traina, F., Koury, L. C., Melo, R. A. M., Bittencourt, R., Pagnano, K., Pasquini, R., ... Rego, E. M. (2020). NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia. Scientific Reports, 10(1), 10315. Article 10315. https://doi.org/10.1038/s41598-020-66223-2

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title = "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 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.",

author = "Thom{\'e}, {Carolina Hassibe} and Ferreira, {Germano Aguiar} and Pereira-Martins, {Diego Antonio} and {Dos Santos}, {Guilherme Augusto} and Ortiz, {C{\'e}sar Alexander} and {de Souza}, {Lucas Eduardo Botelho} and Sobral, {Lays Martins} and Silva, {Cleide L{\'u}cia Ara{\'u}jo} and Scheucher, {Priscila Santos} and Gil, {Cristiane Damas} and Leopoldino, {Andr{\'e}ia Machado} and Silveira, {Douglas R A} and Coelho-Silva, {Juan L} and Fab{\'i}ola Traina and Koury, {Luisa C} and Melo, {Raul A M} and Rosane Bittencourt and Katia Pagnano and Ricardo Pasquini and Nunes, {Elenaide C} and Fagundes, {Evandro M} and Gloria, {Ana Beatriz F} and Kerbauy, {F{\'a}bio Rodrigues} and Chauffaille, {Maria de Lourdes} and Armand Keating and Tallman, {Martin S} and Ribeiro, {Raul C} and Richard Dillon and Arnold Ganser and Bob L{\"o}wenberg and Peter Valk and Francesco Lo-Coco and Sanz, {Miguel A} and Nancy Berliner and Fa{\c c}a, {Vitor Marcel} and Rego, {Eduardo M}",

year = "2020",

month = jun,

day = "25",

doi = "10.1038/s41598-020-66223-2",

language = "English",

volume = "10",

pages = "10315",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

Thomé, CH, Ferreira, GA, Pereira-Martins, DA, Dos Santos, GA, Ortiz, CA, de Souza, LEB, Sobral, LM, Silva, CLA, Scheucher, PS, Gil, CD, Leopoldino, AM, Silveira, DRA, Coelho-Silva, JL, Traina, F, Koury, LC, Melo, RAM, Bittencourt, R, Pagnano, K, Pasquini, R, Nunes, EC, Fagundes, EM, Gloria, ABF, Kerbauy, FR, Chauffaille, MDL, Keating, A, Tallman, MS, Ribeiro, RC, Dillon, R, Ganser, A, Löwenberg, B, Valk, P, Lo-Coco, F, Sanz, MA, Berliner, N, Faça, VM & Rego, EM 2020, 'NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia', Scientific Reports, vol. 10, no. 1, 10315, pp. 10315. https://doi.org/10.1038/s41598-020-66223-2

TY - JOUR

T1 - NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia

AU - Thomé, Carolina Hassibe

AU - Ferreira, Germano Aguiar

AU - Pereira-Martins, Diego Antonio

AU - Dos Santos, Guilherme Augusto

AU - Ortiz, César Alexander

AU - de Souza, Lucas Eduardo Botelho

AU - Sobral, Lays Martins

AU - Silva, Cleide Lúcia Araújo

AU - Scheucher, Priscila Santos

AU - Gil, Cristiane Damas

AU - Leopoldino, Andréia Machado

AU - Silveira, Douglas R A

AU - Coelho-Silva, Juan L

AU - Traina, Fabíola

AU - Koury, Luisa C

AU - Melo, Raul A M

AU - Bittencourt, Rosane

AU - Pagnano, Katia

AU - Pasquini, Ricardo

AU - Nunes, Elenaide C

AU - Fagundes, Evandro M

AU - Gloria, Ana Beatriz F

AU - Kerbauy, Fábio Rodrigues

AU - Chauffaille, Maria de Lourdes

AU - Keating, Armand

AU - Tallman, Martin S

AU - Ribeiro, Raul C

AU - Dillon, Richard

AU - Ganser, Arnold

AU - Löwenberg, Bob

AU - Valk, Peter

AU - Lo-Coco, Francesco

AU - Sanz, Miguel A

AU - Berliner, Nancy

AU - Faça, Vitor Marcel

AU - Rego, Eduardo M

PY - 2020/6/25

Y1 - 2020/6/25

N2 - 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.

AB - 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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U2 - 10.1038/s41598-020-66223-2

DO - 10.1038/s41598-020-66223-2

M3 - Article

C2 - 32587277

SN - 2045-2322

VL - 10

SP - 10315

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10315

ER -

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

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