Nina Orfali1,2,3,4, Tracey R O'Donovan1, Mary R Cahill1,2, Dalyia Benjamin1,2,3, David M Nanus4, Sharon L McKenna1, Lorraine J Gudas3, Nigel P Mongan3,5. 1. Cork Cancer Research Centre & CancerResearch@UCC, Western Gateway Building, University College Cork, Cork, Ireland. 2. Department of Haematology, Cork University Hospital, Cork, Ireland. 3. Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. 4. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA. 5. University of Nottingham Biodiscovery Institute, Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, University of Nottingham, Nottingham, UK.
Abstract
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).
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).
Authors: Jonathan D Lee; Joao A Paulo; Ryan R Posey; Vera Mugoni; Nikki R Kong; Giulia Cheloni; Yu-Ru Lee; Frank J Slack; Daniel G Tenen; John G Clohessy; Steven P Gygi; Pier Paolo Pandolfi Journal: Nat Methods Date: 2021-03-01 Impact factor: 28.547
Authors: Dalyia N Benjamin; Tracey R O'Donovan; Kristian B Laursen; Nina Orfali; Mary R Cahill; Nigel P Mongan; Lorraine J Gudas; Sharon L McKenna Journal: Front Oncol Date: 2022-02-24 Impact factor: 6.244
Authors: Nina Orfali; Deborah Shan-Krauer; Tracey R O'Donovan; Nigel P Mongan; Lorraine J Gudas; Mary R Cahill; Mario P Tschan; Sharon L McKenna Journal: Mol Oncol Date: 2020-05-01 Impact factor: 6.603
Authors: Magali Humbert; Kristina Seiler; Severin Mosimann; Vreni Rentsch; Katyayani Sharma; Amit V Pandey; Sharon L McKenna; Mario P Tschan Journal: Cell Death Differ Date: 2021-03-19 Impact factor: 15.828