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Haematologica. 2019 May 9. pii: haematol.2018.199364. doi: 10.3324/haematol.2018.199364. [Epub ahead of print]

Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia.

Author information

1
Ulm University Medical Center, Ulm, Germany.
2
Dept. of of Obstetrics and Gynecology, Ulm University Medical Center Ulm, Germany.
3
Department of Internal Medicine III, Ulm University Medical Center, Ulm, Germany.
4
Department of Pediatric Oncology and Hematology, Charite' Center Gynecology, Berlin, Germany.
5
University Children's Hospital Tübingen, Germany.
6
Department of Women and Children Health, University of Padova, Padova, Italy.
7
Dept. of Obstetrics and Gynecology, Ulm University Medical Center, Ulm, Germany.
8
Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
9
Dept. of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
10
Dept. of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany lueder-hinrich.meyer@uniklinik-ulm.de.

Abstract

Alterations of the tumor suppressor gene TP53 are found in different cancers, in particular in carcinomas of adults. In pediatric acute lymphoblastic leukemia, TP53 mutations are infrequent but enriched at relapse. As in most cancers, mainly DNA-binding domain missense 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 wild type function by the small molecule APR-246. We investigated TP53 mutations in cell lines and 62 B-cell precursor acute lymphoblastic leukemia samples and evaluated the activity of APR-246 in TP53 mutated or wild type acute lymphoblastic leukemias. We identified cases with TP53 missense mutations, high (mutant) p53 expression and insensitivity to the DNA-damaging agent doxorubicin. In TP53 mutated acute lymphoblastic leukemia, APR-246 induced apoptosis showing strong anti-leukemia activity. APR-246 restored mutant p53 to its wild type 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 contributed to APR-246 mediated cell death. In a pre-clinical model of patient-derived TP53 mutant acute lymphoblastic leukemia, APR-246 reduced leukemia burden and strongly synergized 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 therapeutic strategy for this high-risk group of TP53 mutant acute lymphoblastic leukemia.

KEYWORDS:

Directed therapy; Pediatric Acute Lymphoblastic Leukemia; Preclinical leukemia model

PMID:
31073076
DOI:
10.3324/haematol.2018.199364
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