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

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Thome, Carolina Hassibe ^{[1, 2]} ; Ferreira, Germano Aguiar ^{[1, 2]} ; Pereira-Martins, Diego Antonio ^[2] ; dos Santos, Guilherme Augusto ^[2] ; Ortiz, Cesar Alexander ^[2] ; Botelho de Souza, Lucas Eduardo ^[2] ; Sobral, Lays Martins ^[3] ; Araujo Silva, Cleide Lucia ^[2] ; Scheucher, Priscila Santos ^[2] ; Gil, Cristiane Damas ^[4] ; Leopoldino, Andreia Machado ^[3] ; Silveira, Douglas R. A. ^[5] ; Coelho-Silva, Juan L. ^[2] ; Traina, Fabiola ^[2] ; Koury, Luisa C. ^[2] ; Melo, Raul A. M. ^[6] ; Bittencourt, Rosane ^[7] ; Pagnano, Katia ^[8] ; Pasquini, Ricardo ^[9] ; Nunes, Elenaide C. ^[9] ; Fagundes, Evandro M. ^[10] ; Gloria, Ana Beatriz F. ^[10] ; Kerbauy, Fabio Rodrigues ^[11] ; Chauffaille, Maria de Lourdes ^[11] ; Keating, Armand ^[12] ; Tallman, Martin S. ^[13] ; Ribeiro, Raul C. ^[14] ; Dillon, Richard ^[15] ; Ganser, Arnold ^[16] ; Lowenberg, Bob ^[17] ; Valk, Peter ^[17] ; Lo-Coco, Francesco ^{[18, 19]} ; Sanz, Miguel A. ^{[20, 21]} ; Berliner, Nancy ^[22] ; Faca, Vitor Marcel ^{[1, 2]} ; Rego, Eduardo M. ^{[2, 23]}

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^[1] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Biochem & Immunol, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Reg Blood Ctr Ribeirao Preto, Ctr Cell Based Therapy, Med Sch Ribeirao Preto, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Dept Clin Anal Toxicol & Food Sci, Ribeirao Preto - Brazil

^[4] Univ Fed Sao Paulo, Dept Morphol & Genet, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Med Sch, Hematol, Sao Paulo - Brazil

^[6] Univ Pernambuco, Dept Internal Med, Recife, PE - Brazil

^[7] Univ Fed Rio Grande do Sul, Hematol Div, Porto Alegre, RS - Brazil

^[8] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Campinas - Brazil

^[9] Univ Fed Parana, Hematol Div, Curitiba, Parana - Brazil

^[10] Univ Fed Minas Gerais, Hematol Div, Belo Horizonte, MG - Brazil

^[11] Univ Fed Sao Paulo, Sao Paulo - Brazil

^[12] Princess Margaret Canc Ctr, Cell Therapy Program, Toronto, ON - Canada

^[13] Weill Cornell Med Coll, Leukemia Serv, Mem Sloan Kettering Canc Ctr, New York, NY - USA

^[14] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 - USA

^[15] Kings Coll London, Dept Med & Mol Genet, Sch Med, London - England

^[16] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Hannover - Germany

^[17] Erasmus MC, Dept Hematol, Rotterdam - Netherlands

^[18] Santa Lucia Fdn, Rome - Italy

^[19] Tor Vergata Univ, Dept Biopathol, Rome - Italy

^[20] Univ Valencia, Dept Hematol, Med Sch, Valencia - Spain

^[21] Inst Carlos III, CIBERONC, Madrid - Spain

^[22] Harvard Med Sch, Dept Med, Brigham & Womens Hosp, Boston, MA 02115 - USA

^[23] Univ Sao Paulo, Med Sch, Hematol, LIM31, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 10, n. 1 JUN 25 2020.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 13/07675-3 - Estudo da via de sinalização pi3k/akt em leucemia mielóide aguda utilizando o monitoramento seletivo de ions (srm).
• Beneficiário: Carolina Hassibe Thomé
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 16/03809-3 - Estudo proteômico dirigido da localização e translocação subcelular de proteínas na transição epitélio-mesenquimal
• Beneficiário: Vitor Marcel Faça
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/23117-1 - Avaliação da via TP53/TP73 na enxertia de células de leucemia promielocítica aguda em modelo de xenotransplante
• Beneficiário: Diego Antonio Pereira Martins
• Modalidade de apoio: Bolsas no Brasil - Doutorado