Forced retinoic acid receptor alpha homodimers prime mice for APL-like leukemia.
RARA becomes an acute promyelocytic leukemia (APL) oncogene by fusion with any of five translocation partners. Unlike RARalpha, the fusion proteins homodimerize, which may be central to oncogenic activation. This model was tested by replacing PML with dimerization domains from p50NFkappaB (p50-RARalpha) or the rapamycin-sensitive dimerizing peptide of FKBP12 (F3-RARalpha). The X-RARalpha fusions recapitulated in vitro activities of PML-RARalpha. For F3-RARalpha, these properties were rapamycin sensitive. Although in vivo the artificial fusions alone are poor initiators of leukemia, p50-RARalpha readily cooperates with an activated mutant CDw131 to induce APL-like disease. These results demonstrate that the dimerization interface of RARalpha fusion partners is a critical element in APL pathogenesis while pointing to other features of PML for enhancing penetrance and progression.
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Thomas
T
Sternsdorf
Vernon T
VT
Phan
Mei Lin
ML
Maunakea
Corinne B
CB
Ocampo
Jastinder
J
Sohal
Angela
A
Silletto
Francesco
F
Galimi
Michelle M
MM
Le Beau
Ronald M
RM
Evans
Scott C
SC
Kogan
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002273:Carcinogens / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D018121:Receptors, Cytokine / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D002273:Carcinogens; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C000607072:Rara protein, mouse; D018121:Receptors, Cytokine; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D004247:DNA