title: Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling.
abstract: Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs). APLs with the PML-RAR alpha or the PLZF-RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RAR alpha do not. We here report that (i) like PML-RAR alpha expression, PLZF-RAR alpha expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor beta1, and dimethyl sulfoxide); (ii) PML-RAR alpha, but not PLZF-RAR alpha, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR alpha and PLZF-RAR alpha have similar RA binding affinities; and (iv) PML-RAR alpha enhances the RA response of RA target genes (those for RAR beta, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RAR alpha expression has either no effect (RAR beta) or an inhibitory activity (RAR gamma and type II TGase). These data demonstrate that PML-RAR alpha and PLZF-RAR alpha have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively. Their different activities on the RA signalling pathway might underlie the different responses of PML-RAR alpha and PLZF-RAR alpha APLs to RA treatment. The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions. Deletion of the PLZF POZ domain partially abrogated the inhibitory effect of PLZF-RAR alpha on RA-induced differentiation and on RA-mediated type II TGase up-regulation, suggesting that POZ-mediated protein interactions might be responsible for the inhibitory transcriptional activities of PLZF-RAR alpha.
authors.affiliation: Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia University, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ruthardt
authors.forename: U
authors.initials: U
authors.lastname: Testa
authors.forename: C
authors.initials: C
authors.lastname: Nervi
authors.forename: P F
authors.initials: PF
authors.lastname: Ferrucci
authors.forename: F
authors.initials: F
authors.lastname: Grignani
authors.forename: E
authors.initials: E
authors.lastname: Puccetti
authors.forename: F
authors.initials: F
authors.lastname: Grignani
authors.forename: C
authors.initials: C
authors.lastname: Peschle
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D002762:Cholecalciferol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology; D018922:HL-60 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D011503:Transglutaminases / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D002762:Cholecalciferol; D004268:DNA-Binding Proteins; D004121:Dimethyl Sulfoxide; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D011503:Transglutaminases; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C082925:retinoic acid receptor beta; C092037:ZBTB16 protein, human