All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)
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Date
2019-12-06
Authors
Orfali, Nina
O'Donovan, Tracey R.
Cahill, Mary R.
Benjamin, Dalyia
Nanus, David M.
McKenna, Sharon L.
Gudas, Lorraine J.
Mongan, Nigel P.
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Publisher
John Wiley & Sons, Inc.
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Abstract
Objective: In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RAR alpha 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-RAR alpha 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).
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Keywords
Acute myeloid leukemia , Autophagy , Hematopoiesis , Differentiation , Retinoid , Transcription factor EB
Citation
Orfali, N., O'Donovan, T. R., Cahill, M. R., Benjamin, D., Nanus, D. M., McKenna, S. L., Gudas, L. J. and Mongan, N. P. (2019) 'All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)', European Journal of Haematology, 104(3), pp. 151-278. doi: 10.1111/ejh.13367
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© 2019, John Wiley & Sons Ltd. This is the accepted version of the following item: Orfali, N., O'Donovan, T. R., Cahill, M. R., Benjamin, D., Nanus, D. M., McKenna, S. L., Gudas, L. J. and Mongan, N. P. (2019) 'All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)', European Journal of Haematology, 104(3), pp. 151-278, doi: 10.1111/ejh.13367, which has been published in final form at: https://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.