The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.
Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 944, Equipe labellisée par la Ligue Nationale contre le Cancer, 2 University Paris-Diderot, Sorbonne Paris Cité, Paris, France. hugues.dethe@inserm.fr
Hugues
H
de Thé
Morgane
M
Le Bras
Valérie
V
Lallemand-Breitenbach
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001151:Arsenic / Q000627:therapeutic use*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014212:Tretinoin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D025841:Small Ubiquitin-Related Modifier Proteins; D014212:Tretinoin; D001151:Arsenic