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Maifrede S , Martin K , Podszywalow-Bartnicka P , Sullivan-Reed K , Langer SK , Nejati R , Dasgupta Y , Hulse M , Gritsyuk D , Nieborowska-Skorska M , Lupey-Green LN , Zhao H , Piwocka K , Wasik MA , Tempera I , Skorski T
IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors
Mol Cancer Res. 2017 Aug;15(8) :967-972
PMID: 28634224    PMCID: PMC5540764   
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Abstract
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.jpgMol Cancer Res; 15(8); 967-72. (c)2017 AACR.
Notes
1557-3125 Maifrede, Silvia Martin, Kayla Podszywalow-Bartnicka, Paulina Sullivan-Reed, Katherine Langer, Samantha K Nejati, Reza Dasgupta, Yashodhara Hulse, Michael Gritsyuk, Daniel Nieborowska-Skorska, Margaret Lupey-Green, Lena N Zhao, Huaqing Piwocka, Katarzyna Wasik, Mariusz A Tempera, Italo Skorski, Tomasz R01 CA186238/CA/NCI NIH HHS/United States Journal Article United States Mol Cancer Res. 2017 Aug;15(8):967-972. doi: 10.1158/1541-7786.MCR-16-0468. Epub 2017 Jun 20.