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All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)

Orfali, Nina; O'Donovan, Tracey R.; Cahill, Mary R.; Benjamin, Dalyia; Nanus, David M.; McKenna, Sharon L.; Gudas, Lorraine J.; Mongan, Nigel P.

All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL) Thumbnail


Authors

Nina Orfali

Tracey R. O'Donovan

Mary R. Cahill

Dalyia Benjamin

David M. Nanus

Sharon L. McKenna

Lorraine J. Gudas

NIGEL MONGAN nigel.mongan@nottingham.ac.uk
Professor of Oncology



Abstract

© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all-trans-retinoic acid (ATRA) can restore retinoid-induced transcription and promote degradation of the PML-RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re-modeling. Recent studies have identified autophagy as an integral component of ATRA-induced myeloid differentiation. Methods: As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy-related transcripts. Results: ATRA altered the expression of >80 known autophagy-related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5-fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA-resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA. Conclusions: We show for the first time that TFEB plays an important role in ATRA-induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156).

Citation

Orfali, N., O'Donovan, T. R., Cahill, M. R., Benjamin, D., Nanus, D. M., McKenna, S. L., …Mongan, N. P. (2020). All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL). European Journal of Haematology, 104(3), 236-250. https://doi.org/10.1111/ejh.13367

Journal Article Type Article
Acceptance Date Feb 18, 2019
Online Publication Date Jan 13, 2020
Publication Date 2020-03
Deposit Date Feb 22, 2019
Publicly Available Date Jan 14, 2021
Journal European Journal of Haematology
Print ISSN 0902-4441
Electronic ISSN 1600-0609
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 104
Issue 3
Pages 236-250
DOI https://doi.org/10.1111/ejh.13367
Public URL https://nottingham-repository.worktribe.com/output/1579248
Publisher URL https://onlinelibrary.wiley.com/doi/full/10.1111/ejh.13367
Additional Information This is the peer reviewed version of the following article: Orfali, N, O'Donovan, TR, Cahill, MR, et al. All?trans retinoic acid (ATRA)?induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL). Eur J Haematol. 2019, which has been published in final form athttps://doi.org/10.1111/ejh.13367. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.

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