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

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

doi:10.1111/ejh.13367

Abstract

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. 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. 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. 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).

Highlights

Retinoids are signaling molecules related to Vitamin A that have well-established roles in development and differentiation.[1]
RNA sequencing of all-trans-retinoic acid (ATRA)-treated acute promyelocytic leukemia (APL) cells confirms activation of a myeloid differentiation program We and others have recently shown that autophagy plays a role in the NB4 model of APL differentiation.[11]
We found that ATRA-treated NB4 cells showed decreased GATA2 mRNA levels and we observed a similar decrease in transcripts for MYC, another transcription factor associated with an undifferentiated state (Figure 1B).[34]

Summary

Introduction

Retinoids are signaling molecules related to Vitamin A (retinol) that have well-established roles in development and differentiation.[1] Dietary retinoids are metabolized within cells to a bioactive form, all-trans-retinoic acid (ATRA), which exerts its effects by mediating gene transcription.[1] ATRA binds retinoic acid receptors (RARs) and rexinoid receptors (RXRs) These liganddependent transcription factors form RXR-RAR heterodimers that preferentially bind to specific DNA sequence motifs, termed retinoic acid response elements (RAREs), in the promoters or enhancers of target genes.[1] Through interactions with diverse, co-regulatory proteins the RXRRAR complexes regulate transcription.[2] Acute promyelocytic leukemia (APL), a distinct subtype of acute myeloid leukemia (AML), is defined by the clonal proliferation of granulocyte precursors halted at the promyelocyte stage of development.[3] Cytogenetically, APL is distinguished by a chromosomal translocation affecting the RARα gene locus on chromosome 17q21 in malignant clones,[4] most commonly generating the functional PML-RARα fusion oncogene.[4] The PML-RARα oncoprotein binds to RAREs on retinoid target gene promoters. Our data implicates TFEB as an important mediator of ATRA-induced differentiation in APL

Methods

Results

Conclusion