title: ΔNp73 overexpression promotes resistance to apoptosis but does not cooperate with PML/RARA in the induction of an APL-leukemic phenotype.
abstract: Here, we evaluated whether the overexpression of transcriptionally inactive ΔNp73 cooperates with PML/RARA fusion protein in the induction of an APL-leukemic phenotype, as well as its role in vitro in proliferation, myeloid differentiation, and drug-induced apoptosis. Using lentiviral gene transfer, we showed in vitro that ΔNp73 overexpression resulted in increased proliferation in murine bone marrow (BM) cells from hCG-PML/RARA transgenic mice and their wild-type (WT) counterpart, with no accumulation of cells at G2/M or S phases; instead, ΔNp73-expressing cells had a lower rate of induced apoptosis. Next, we evaluated the effect of ΔNp73 on stem-cell self-renewal and myeloid differentiation. Primary BM cells lentivirally infected with human ΔNp73 were not immortalized in culture and did not present significant changes in the percentage of CD11b. Finally, we assessed the impact of ΔNp73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype. After 120 days of follow-up, all transplanted mice were clinically healthy and, no evidence of leukemia/myelodysplasia was apparent. Taken together, our data suggest that ΔNp73 had no leukemic transformation capacity by itself and apparently did not cooperate with the PML/RARA fusion protein to induce a leukemic phenotype in a murine BM transplantation model. In addition, the forced expression of ΔNp73 in murine BM progenitors did not alter the ATRA-induced differentiation rate in vitro or induce aberrant cell proliferation, but exerted an important role in cell survival, providing resistance to drug-induced apoptosis.
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto, Brazil.|Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Lucena-Araujo
authors.affiliation: Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Coelho-Silva
authors.affiliation: Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Pereira-Martins
authors.affiliation: Center for Cell Based Therapy, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Thomé
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto, Brazil.
authors.forename: Priscila S
authors.initials: PS
authors.lastname: Scheucher
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Lange
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto, Brazil.
authors.forename: Helder H
authors.initials: HH
authors.lastname: Paiva
authors.affiliation: The Ohio State University, Columbus, USA.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Hemmelgarn
authors.affiliation: Department of Microbiology, Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, Recife, Brazil.
authors.forename: Mariana C
authors.initials: MC
authors.lastname: Morais-Sobral
authors.affiliation: Department of Virology, Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, Recife, Brazil.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Azevedo
authors.affiliation: Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Franca-Neto
authors.affiliation: Department of Virology, Fundação Oswaldo Cruz, Centro de Pesquisas Aggeu Magalhães, Recife, Brazil.
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Franca
authors.affiliation: Center for Cell Based Therapy, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Cleide L
authors.initials: CL
authors.lastname: Silva
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Krause
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto, Brazil.|Center for Cell Based Therapy, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Rego
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation; D056649:Cathepsin G / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic; D020022:Genetic Predisposition to Disease; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000072160:Tumor Protein p73 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000964:Antimetabolites, Antineoplastic; D000071156:Promyelocytic Leukemia Protein; D000072482:Retinoic Acid Receptor alpha; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D003561:Cytarabine; C534094:CTSG protein, human; D056649:Cathepsin G
keywords: acute promyelocytic leukemia; apoptosis; bone marrow transplantation; lentiviral gene transfer; ΔNp73