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.

• 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
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 10315 (06 25 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32587277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Anthracyclines
• LAT2 protein, human
• Tretinoin

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Adolescent
• Adult
• Aged
• Animals
• Anthracyclines (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Bone Marrow (pathology)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease-Free Survival
• Female
• Gene Knockdown Techniques
• Humans
• Leukemia, Promyelocytic, Acute (blood, drug therapy, mortality, pathology)
• Leukocyte Count
• Male
• Membrane Microdomains (metabolism)
• Mice
• Middle Aged
• Retrospective Studies
• Survival Analysis
• Tretinoin (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays
• Young Adult