title: Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa-associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center; and 2 Department of Medicine and 3 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Guilherme Augusto
authors.initials: GA
authors.lastname: Dos Santos
authors.forename: Lev
authors.initials: L
authors.lastname: Kats
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000737:chemistry; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D010087:Oxides / Q000737:chemistry; D012074:Remission Induction; D015398:Signal Transduction; D015533:Transcriptional Activation; D014212:Tretinoin / Q000737:chemistry
chemical_list: D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide