title: High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia.
abstract: The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil;
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Lucena-Araujo
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil;
authors.forename: Carolina
authors.initials: C
authors.lastname: Thomé
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil;
authors.forename: Rafael H
authors.initials: RH
authors.lastname: Jacomo
authors.affiliation: Department of Internal Medicine, University of Pernambuco and Fundação HEMOPE, Recife, Brazil;
authors.forename: Raul A
authors.initials: RA
authors.lastname: Melo
authors.affiliation: Hematology Division, Federal University of Rio Grande do Sul, Porto Alegre, Brazil;
authors.forename: Rosane
authors.initials: R
authors.lastname: Bittencourt
authors.affiliation: Hematology Division, Federal University of Paraná, Curitiba, Brazil;
authors.forename: Ricardo
authors.initials: R
authors.lastname: Pasquini
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil;
authors.forename: Katia
authors.initials: K
authors.lastname: Pagnano
authors.affiliation: Hematology Division, Federal University of Minas Gerais, Belo Horizonte, Brazil;
authors.forename: Ana Beatriz F
authors.initials: AB
authors.lastname: Glória
authors.affiliation: Hematology and Transfusion Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Chauffaille
authors.affiliation: Hematology Division, Federal University of Minas Gerais, Belo Horizonte, Brazil;
authors.forename: Melina
authors.initials: M
authors.lastname: Athayde
authors.affiliation: Hematology Division, Santa Casa Medical School, Sao Paulo, Brazil;
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Chiattone
authors.affiliation: Hematology Division, Federal University of Rio Grande do Sul, Porto Alegre, Brazil;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Mito
authors.affiliation: Hematology Division, Federal University of Paraná, Curitiba, Brazil;
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Bendlin
authors.affiliation: Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil;
authors.forename: Carmino
authors.initials: C
authors.lastname: Souza
authors.affiliation: Hematology Division, Santa Casa Medical School, Sao Paulo, Brazil;
authors.forename: Cristina
authors.initials: C
authors.lastname: Bortolheiro
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 Medicine, Stanford University, Stanford, CA;
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Schrier
authors.affiliation: Leukemia Service, Memorial Sloan Kettering Cancer Center/Weill Cornell Medical College, New York, NY;
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom;
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.affiliation: Department of Hematology, Hannover Medical School, Hannover, Germany;
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
authors.forename: Nancy
authors.initials: N
authors.lastname: Berliner
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.affiliation: Department of Biopathology, University Tor Vergata, Rome, Italy; Santa Lucia Foundation, Rome, Italy;
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; and.
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Department of Hematology, Valencia University Medical School, Valencia, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sanz
authors.affiliation: Department of Internal Medicine, Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil;
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Rego
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D002648:Child; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D016016:Proportional Hazards Models; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D015996:Survival Rate; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human