Lucena-Araujo Antonio R, Kim Haesook T, Thomé Carolina, Jacomo Rafael H, Melo Raul A, Bittencourt Rosane, Pasquini Ricardo, Pagnano Katia, Glória Ana Beatriz F, Chauffaille Maria de Lourdes, Athayde Melina, Chiattone Carlos S, Mito Ingrid, Bendlin Rodrigo, Souza Carmino, Bortolheiro Cristina, Coelho-Silva Juan L, Schrier Stanley L, Tallman Martin S, Grimwade David, Ganser Arnold, Berliner Nancy, Ribeiro Raul C, Lo-Coco Francesco, Löwenberg Bob, Sanz Miguel A, Rego Eduardo M
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;
Blood. 2015 Nov 12;126(20):2302-6. doi: 10.1182/blood-2015-01-623330. Epub 2015 Oct 1.
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.
TP73基因转录本可发生可变剪接，并被翻译为具有转录活性的（TAp73）或无活性的（ΔNp73）异构体，它们对p53靶基因的表达及凋亡诱导具有相反的作用。ΔNp73与TAp73之间的失衡可能促成包括血液系统恶性肿瘤在内的人类癌症的肿瘤发生及化疗耐药。在急性早幼粒细胞白血病（APL）中，两种异构体均有表达，但其在决定治疗反应及白血病发生中的相关性仍不清楚。在此，根据国际急性早幼粒细胞白血病联盟（IC-APL）研究，我们首次提供证据表明，在接受全反式维甲酸和蒽环类药物化疗的APL患者中，较高的ΔNp73/TAp73 RNA表达比值与较低的生存率、无病生存率及较高的复发风险相关。Cox比例风险模型显示，高ΔNp73/TAp73比值与较短的总生存期独立相关（风险比，4.47；95%置信区间，1.64至12.2；P = 0.0035）。我们的数据支持以下假说，即ΔNp73/TAp73比值是APL临床反应的重要决定因素，并且可能为提高原始细胞的化疗敏感性提供一个治疗靶点。
