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Ferrata Storti Foundation
Haematologica 2020 Volume 105(1):170-181
Acute Lymphoblastic Leukemia
Therapeutic targeting of mutant p53
in pediatric acute lymphoblastic leukemia
Salih Demir,1,2 Elena Boldrin,1,2,3 Qian Sun,1 Stephanie Hampp,4 Eugen Tausch,5 Cornelia Eckert,6 Martin Ebinger,7 Rupert Handgretinger,7 Geertruy te Kronnie,8 Lisa Wiesmüller,4 Stephan Stilgenbauer,5 Galina Selivanova,9 Klaus-Michael Debatin1 and Lüder Hinrich Meyer1
1Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany; 2International Graduate School of Molecular Medicine, Ulm University, Ulm, Germany; 3PhD Program in Biosciences, University of Padova, Padova, Italy; 4Department of Obstetrics and Gynecology, Ulm University Medical Center, Ulm, Germany; 5Department of Internal Medicine III, Ulm University Medical Center, Ulm, Germany; 6Department of Pediatrics, Charité Center Gynecology, Perinatal, Pediatric and Adolescent Medicine, Berlin, Germany; 7Department of General Pediatrics, Hematology and Oncology, Children's University Hospital Tübingen, Tübingen, Germany; 8Department of Women’s and Children’s Health, University of Padova, Padova, Italy and 9Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
ABSTRACT
Alterations of the tumor suppressor gene TP53 are found in different cancers, in particular in carcinomas of adults. In pediatric acute lym- phoblastic leukemia (ALL), TP53 mutations are infrequent but enriched at relapse. As in most cancers, mainly DNA-binding domain mis- sense mutations are found, resulting in accumulation of mutant p53, poor therapy response, and inferior outcome. Different strategies to target mutant p53 have been developed including reactivation of p53’s wildtype function by the small molecule APR-246. We investigated TP53 mutations in cell lines and 62 B-cell precursor ALL samples and evaluated the activity of APR-246 in TP53-mutated or wildtype ALL. We identified cases with TP53 missense mutations, high (mutant) p53 expression and insensitivity to the DNA-damaging agent doxorubicin. In TP53-mutated ALL, APR-246 induced apoptosis showing strong anti-leukemia activity. APR-246 restored mutant p53 to its wildtype conformation, leading to pathway activation with induction of transcriptional targets and re-sensitization to genotoxic therapy in vitro and in vivo. In addition, induction of oxidative stress con- tributed to APR-246-mediated cell death. In a preclinical model of patient- derived TP53-mutant ALL, APR-246 reduced leukemia burden and syner- gized strongly with the genotoxic agent doxorubicin, leading to superior leukemia-free survival in vivo. Thus, targeting mutant p53 by APR-246, restoring its tumor suppressive function, seems to be an effective therapeu- tic strategy for this high-risk group of TP53-mutant ALL.
Introduction
Although most pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) have a favorable prognosis, achievement of long-term survival remains a major clinical challenge, particularly at relapse.1 Alterations of cell death programs cause treatment failure and resistance in many cancers including leukemia. The nuclear phosphoprotein p53 is a transcription factor that controls cellular respons- es to stress, including DNA damage. Originally identified more than three decades ago,2,3 p53 was characterized as a tumor suppressor negatively regulating cell cycle and growth, inhibiting the cancer cell’s oncogenic potential.4,5 The gene coding for p53 (TP53) is localized on the short arm of chromosome 17 (17p13) and it is the most frequently mutated gene across different cancers.6,7 Both deletions and point mutations have been described and mutations often co-occur with loss of the cor- responding wildtype allele.8,9 The majority are TP53 missense mutations found within the DNA-binding domain coding region (codons 100-300, exons 5-8) and
Correspondence:
LÜDER HINRICH MEYER
lueder-hinrich.meyer@uniklinik-ulm.de
Received: June 25, 2018. Accepted: May 2, 2019. Pre-published: May 9, 2019.
doi:10.3324/haematol.2018.199364
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