title: A bcr-3 isoform of RARalpha-PML potentiates the development of PML-RARalpha-driven acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APML) most often is associated with the balanced reciprocal translocation t(15;17) (q22;q11.2) and the expression of both the PML-RARalpha and RARalpha-PML fusion cDNAs that are formed by this translocation. In this report, we investigated the biological role of a bcr-3 isoform of RARalpha-PML for the development of APML in a transgenic mouse model. Expression of RARalpha-PML alone in the early myeloid cells of transgenic mice did not alter myeloid development or cause APML, but its expression significantly increased the penetrance of APML in mice expressing a bcr-1 isoform of PML-RARalpha (15% of animals developed APML with PML-RARalpha alone vs. 57% with both transgenes, P < 0.001). The latency of APML development was not altered substantially by the expression of RARalpha-PML, suggesting that it does not behave as a classical "second hit" for development of the disease. Leukemias that arose from doubly transgenic mice were less mature than those from PML-RARalpha transgenic mice, but they both responded to all-trans retinoic acid in vitro. These findings suggest that PML-RARalpha drives the development of APML and defines its basic phenotype, whereas RARalpha-PML potentiates this phenotype via mechanisms that are not yet understood.
authors.affiliation: Washington University School of Medicine, Division of Bone Marrow Transplantation, Department of Internal Medicine, St. Louis, MO 63110, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Pollock
authors.forename: P
authors.initials: P
authors.lastname: Westervelt
authors.forename: A K
authors.initials: AK
authors.lastname: Kurichety
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.forename: J L
authors.initials: JL
authors.lastname: Grisolano
authors.forename: T J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002403:Cathepsins / Q000235:genetics; D003433:Crosses, Genetic; D015870:Gene Expression; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019683:Penetrance; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D002403:Cathepsins