ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression.
Tightly regulated expression of the transcription factor PU.1 is crucial for normal hematopoiesis. PU.1 knockdown mice develop acute myeloid leukemia (AML), and PU.1 mutations have been observed in some populations of patients with AML. Here we found that conditional expression of promyelocytic leukemia-retinoic acid receptor alpha (PML-RARA), the protein encoded by the t(15;17) translocation found in acute promyelocytic leukemia (APL), suppressed PU.1 expression, while treatment of APL cell lines and primary cells with all-trans retinoic acid (ATRA) restored PU.1 expression and induced neutrophil differentiation. ATRA-induced activation was mediated by a region in the PU.1 promoter to which CEBPB and OCT-1 binding were induced. Finally, conditional expression of PU.1 in human APL cells was sufficient to trigger neutrophil differentiation, whereas reduction of PU.1 by small interfering RNA (siRNA) blocked ATRA-induced neutrophil differentiation. This is the first report to show that PU.1 is suppressed in acute promyelocytic leukemia, and that ATRA restores PU.1 expression in cells harboring t(15;17).
Mueller
Beatrice U
BU
Department of Internal Medicine, University Hospital, 3010 Bern, Switzerland. beatrice.mueller@insel.ch
Pabst
Thomas
T
Fos
José
J
Petkovic
Vibor
V
Fey
Martin F
MF
Asou
Norio
N
Buergi
Ulrich
U
Tenen
Daniel G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D050811:Octamer Transcription Factor-1 / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D000099232:Proto-Oncogene Protein Spi-1
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D050811:Octamer Transcription Factor-1; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein