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.

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.