IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors.

Autor:	Maifrede S; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Martin K; Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Podszywalow-Bartnicka P; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.; Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland., Sullivan-Reed K; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Langer SK; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Nejati R; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Dasgupta Y; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Hulse M; Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Gritsyuk D; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Nieborowska-Skorska M; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Lupey-Green LN; Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania., Zhao H; Temple University Lewis Katz School of Medicine, Department of Clinical Sciences, Philadelphia, Pennsylvania., Piwocka K; Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland., Wasik MA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Tempera I; Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania. tskorski@temple.edu tempera@temple.edu., Skorski T; Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania. tskorski@temple.edu tempera@temple.edu.; Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2017 Aug; Vol. 15 (8), pp. 967-972. Date of Electronic Publication: 2017 Jun 20.
DOI:	10.1158/1541-7786.MCR-16-0468
Abstrakt:	Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC-positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies. Implications: This study postulates that IGH/MYC-induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg Mol Cancer Res; 15(8); 967-72. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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