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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.

SUBMITTER: Thome CH

PROVIDER: S-EPMC7316767 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Thomé Carolina Hassibe CH Ferreira Germano Aguiar GA Pereira-Martins Diego Antonio DA Dos Santos Guilherme Augusto GA Ortiz César Alexander CA de Souza Lucas Eduardo Botelho LEB Sobral Lays Martins LM Silva Cleide Lúcia Araújo CLA Scheucher Priscila Santos PS Gil Cristiane Damas CD Leopoldino Andréia Machado AM Silveira Douglas R A DRA Coelho-Silva Juan L JL Traina Fabíola F Koury Luisa C LC Melo Raul A M RAM Bittencourt Rosane R Pagnano Katia K Pasquini Ricardo R Nunes Elenaide C EC Fagundes Evandro M EM Gloria Ana Beatriz F ABF Kerbauy Fábio Rodrigues FR Chauffaille Maria de Lourdes ML Keating Armand A Tallman Martin S MS Ribeiro Raul C RC Dillon Richard R Ganser Arnold A Löwenberg Bob B Valk Peter P Lo-Coco Francesco F Sanz Miguel A MA Berliner Nancy N Faça Vitor Marcel VM Rego Eduardo M EM

Scientific reports 20200625 1

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 (ATR ...[more]

PMID: 32587277

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Project description:Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-trans retinoic acid (ATRA)-induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the PI3P-dependent autophagic activity during neutrophil differentiation, and that PU.1-dependent WIPI-1 expression is significantly repressed in primary AML patient samples and that the induction of autophagic flux is associated with neutrophil differentiation of APL cells.

Dataset Information

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

Publications

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

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