Retinoid receptor signaling and autophagy in acute promyelocytic leukemia.
Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.
Cork Cancer Research Center, University College Cork, Cork, Ireland; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
Nina
N
Orfali
Cork Cancer Research Center, University College Cork, Cork, Ireland.
Sharon L
SL
McKenna
Department of Hematology, Cork University Hospital, Cork, Ireland.
Mary R
MR
Cahill
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.. Electronic address: ljgudas@med.cornell.edu.
Lorraine J
LJ
Gudas
Faculty of Medicine and Health Science, School of Veterinary Medicine and Science, University of Nottingham, LE12 5RD, United Kingdom; Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.. Electronic address: nigel.mongan@nottingham.ac.uk.
Nigel P
NP
Mongan
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D012176:Retinoids / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
D018168:Receptors, Retinoic Acid; D012176:Retinoids
AML; APL; ATRA; Arsenic trioxide; Autophagy; Differentiation; Hematopoiesis; PML–RARα; Retinoid