High Delta Np73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

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Lucena-Araujo, Antonio R. ^{[1, 2]} ; Kim, Haesook T. ^[3] ; Thome, Carolina ^{[1, 2]} ; Jacomo, Rafael H. ^{[1, 2]} ; Melo, Raul A. ^{[4, 5]} ; Bittencourt, Rosane ^[6] ; Pasquini, Ricardo ^[7] ; Pagnano, Katia ^[8] ; Gloria, Ana Beatriz F. ^[9] ; Chauffaille, Maria de Lourdes ^[10] ; Athayde, Melina ^[9] ; Chiattone, Carlos S. ^[11] ; Mito, Ingrid ^[6] ; Bendlin, Rodrigo ; Souza, Carmino ; Bortolheiro, Cristina ^[11] ; Coelho-Silva, Juan L. ^[12] ; Schrier, Stanley L. ^[13] ; Tallman, Martin S. ^[14] ; Grimwade, David ^[15] ; Ganser, Arnold ^[16] ; Berliner, Nancy ^[17] ; Ribeiro, Raul C. ^[18] ; Lo-Coco, Francesco ^{[19, 20]} ; Lowenberg, Bob ^{[20, 21]} ; Sanz, Miguel A. ^[22] ; Rego, Eduardo M. ^{[1, 2]}

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^[1] Univ Sao Paulo, Ctr Cell Based Therapy, BR-14048900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Internal Med, BR-14048900 Ribeirao Preto, SP - Brazil

^[3] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 - USA

^[4] Fundacao HEMOPE, Recife, PE - Brazil

^[5] Univ Pernambuco, Dept Internal Med, Recife, PE - Brazil

^[6] Univ Fed Rio Grande do Sul, Div Hematol, Porto Alegre, RS - Brazil

^[7] Univ Fed Parana, Div Hematol, BR-80060000 Curitiba, Parana - Brazil

^[8] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, Campinas, SP - Brazil

^[9] Univ Fed Minas Gerais, Div Hematol, Belo Horizonte, MG - Brazil

^[10] Univ Fed Sao Paulo, Hematol & Transfus Med, Sao Paulo - Brazil

^[11] Santa Casa Med Sch, Div Hematol, Sao Paulo - Brazil

^[12] Univ Fed Pernambuco, Dept Genet, Recife, PE - Brazil

^[13] Stanford Univ, Dept Med, Stanford, CA 94305 - USA

^[14] Mem Sloan Kettering Canc Ctr, Weill Cornell Med Coll, Leukemia Serv, New York, NY 10021 - USA

^[15] Kings Coll London, Sch Med, Dept Med & Mol Genet, London WC2R 2LS - England

^[16] Hannover Med Sch, Dept Hematol, Hannover - Germany

^[17] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 - USA

^[18] St Jude Childrens Res Hosp, Dept Oncol, Memphis, TN 38105 - USA

^[19] Univ Roma Tor Vergata, Dept Biopathol, Rome - Italy

^[20] Santa Lucia Fdn, Rome - Italy

^[21] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam - Netherlands

^[22] Univ Valencia, Sch Med, Dept Hematol, Valencia - Spain

• Tipo de documento: Artigo Científico
• Fonte: Blood; v. 126, n. 20, p. 2302-2306, NOV 12 2015.
• Citações Web of Science: 11

Resumo

The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (Delta Np73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between Delta Np73 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 Delta Np73/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 Delta Np73/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 Delta Np73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells. (AU)

• Processo FAPESP: 07/55067-1 - Analise in vivo e in vitro da acao oncogenica da forma delta n do gene p73 na leucemia promielocitica aguda.
• Beneficiário: Antonio Roberto Lucena de Araújo
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs