Clinical and Functional Studies Reveal That TP73 Isoforms Levels Are Associated with Prognosis and RA-Resistance in Acute Promyelocytic Leukemia
2019
Background: TP73 isoforms gained particular relevance in acute promyelocytic leukemia (APL) since Bernasola et al (JEM. 2004) demonstrated that TAp73 was directly regulated by the PML protein in the nuclear body. The isoforms differ in their transcriptional activity, with those lacking domains in the N-terminal part of the protein exerting a dominant negative effect on TP73 function. In a retrospective analysis of patients with APL treated in ICAPL study, Lucena-Araujo et al (Blood 2015) demonstrated the association between higher ΔNp73/TAp73 ratio values and poor clinical outcome. However,there is a diversity of TP73 isoforms and specially those lacking N-terminal domains (e.g.ΔEx2p73, ΔEx2-3p73 and ΔN'p73) may be relevant in APL genesis and therapy response. Aims: Here, we quantified transcript levels of TP73 N-terminal variants TAp73, ΔNp73, ΔEx2p73, ΔEx2-3p73 and ΔN'p73, as well as the C-terminal variants TP73αand TP73β, and determined whether there is a prognostic correlation. In addition, we evaluated the effect of ΔNp73overexpression on APL cell lines survival and differentiation in vitro and in vivo. Methods: Bone marrow (BM) samples from 98 patients (age, 18-74y) with newly diagnosed APL enrolled in the International Consortium on Acute Leukemia (ICAPL2006) were included. For comparison, BM mononuclear cells from 14 healthy donors (age, 18-60y) were also included. TP73 transcripts were determined by qPCR and using survival ROC curve analysis and the C-index we dichotomized patients into “low” and “high” expression. Proportional hazard model on overall survival (OS) and disease-free survival (DFS) was performed to evaluate prognosis. In addition, empty vector (EV) or ΔNp73α was transduced in NB4 and NB4R2 (RA-resistant) APL cell lines using a lentivirus system. The apoptosis rate was evaluated in both cell lines upon ATO (1 μM) treatment for 24, 48 and 72h. ΔNp73α, cleaved caspase 3 and Bcl-2 protein abundance was detected by western blotting. Granulocytic differentiation induced by RA-treatment (1 μM) alone or in combination with ATO (1 μM) for 72 h was assessed by CD11b surface levels. Finally, lethally irradiated 8-12 week old C57/BL6 Boy (CD45.1) were transplanted with hCG-PMLRARa Blasts (CD45.2) ΔNp73α or EV transduced (ΔNp73α group=16 and EV group=12). Results: Compared to normal BM, APL patients presented higher levels of ΔNp73 (p=.004), ΔEx2p73 (p=.008), and TP73β (p .05) or disease progression in ΔNp73α blasts compared to the control group (p=.095). Conclusions: Our results suggest that transcript levels of ΔNp73, ΔEx2p73 and TAp73 predict outcomes in APL patients treated with RA plus chemotherapy. Additionally, RA plus ATO combination therapy seemed to overcome the effect of ΔNp73 overexpression in vitro. Disclosures Figueiredo-Pontes: Novartis: Honoraria. Pagnano: Abbvie: Consultancy; Sandoz: Consultancy; Pint Pharma: Consultancy. Tallman: Danbury Hospital Tumor Board: Honoraria; 14th Annual Miami Cancer Meeting: Honoraria; International Conference in Leukemia: Honoraria; KAHR: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Nohla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; New Orleans Summer Cancer Conference: Honoraria; Indy Hematology Review: Honoraria; Mayo Clinic: Honoraria; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Salzberg Weill Cornall MSKCC Seminar in Hematologic Malignancies: Honoraria; Hematology Oncology of Indiana: Honoraria; ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Cellerant Therapeutics: Research Funding; University of Oklahoma Medical Center: Honoraria; Bioline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Dillon: Abbvie: Consultancy, Honoraria; TEVA: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Lowenberg: Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board “European Oncology & Haematology”: Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Up-to-Date“, section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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