A sumoylation site in PML/RARA is essential for leukemic transformation.
Pathogenesis of acute promyelocytic leukemia (APL) has been proposed to involve transcriptional repression through enhanced corepressors binding onto RARA moieties of PML/RARA homodimers. Unexpectedly, we show that the K160 sumoylation site in the PML moiety of PML/RARA is required for efficient immortalization/differentiation arrest ex vivo, implying that RARA homodimerization is insufficient to fully immortalize primary hematopoietic progenitor cells. Similarly, PML/RARAK160R transgenic mice develop myeloproliferative syndromes, but never APL. The Daxx repressor no longer binds PML/RARAK160R, but fusion of these two proteins restores the differentiation block ex vivo. Thus, transcriptional repression dependent on a specific sumoylation site in PML is critical for the APL phenotype, while forced RARA dimerization could control expansion of the myeloid compartment.
Zhu
Jun
J
CNRS UPR 9051, laboratoire associé N11 du comité de Paris de la Ligue contre le Cancer, affilié à l'Université de Paris VII, Hôpital St. Louis, 1 avenue Claude Vellefaux, 75475 Paris, Cedex 10, France.
Zhou
Jun
J
Peres
Laurent
L
Riaucoux
Florence
F
Honoré
Nicole
N
Kogan
Scott
S
de Thé
Hugues
H
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
D018076:DNA, Complementary; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human