High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia.

Antonio R Lucena-Araujo, Haesook T Kim, Carolina Thomé, Rafael H Jacomo, Raul A Melo, Rosane Bittencourt, Ricardo Pasquini, Katia Pagnano, Ana Beatriz F Glória, Maria de Lourdes Chauffaille, Melina Athayde, Carlos S Chiattone, Ingrid Mito, Rodrigo Bendlin, Carmino Souza, Cristina Bortolheiro, Juan L Coelho-Silva, Stanley L Schrier, Martin S Tallman, David Grimwade, Arnold Ganser, Nancy Berliner, Raul C Ribeiro, Francesco Lo-Coco, Bob Löwenberg, Miguel A Sanz, Eduardo M Rego

Journal: Blood 2016;126(20):2302-6

PMID: 26429976

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.

© 2015 by The American Society of Hematology.

Address: Department of Internal Medicine, Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil;; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;; Department of Internal Medicine, University of Pernambuco and Fundação HEMOPE, Recife, Brazil;; Hematology Division, Federal University of Rio Grande do Sul, Porto Alegre, Brazil;; Hematology Division, Federal University of Paraná, Curitiba, Brazil;; Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil;; Hematology Division, Federal University of Minas Gerais, Belo Horizonte, Brazil;; Hematology and Transfusion Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;; Hematology Division, Santa Casa Medical School, Sao Paulo, Brazil;; Department of Genetics, Federal University of Pernambuco, Recife, Brazil;; Department of Medicine, Stanford University, Stanford, CA;; Leukemia Service, Memorial Sloan Kettering Cancer Center/Weill Cornell Medical College, New York, NY;; Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom;; Department of Hematology, Hannover Medical School, Hannover, Germany;; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN;; Department of Biopathology, University Tor Vergata, Rome, Italy; Santa Lucia Foundation, Rome, Italy;; Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; and.; Department of Hematology, Valencia University Medical School, Valencia, Spain.
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