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| The Journal of clinical investigation. 2017 May 8. pii: 90825. doi: 10.1172/JCI90825 |
| Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells. |
| Nieborowska-Skorska M1, Sullivan K2, Dasgupta Y3, Podszywalow-Bartnicka P4, Hoser G5, Maifrede S6, Martinez E7, Di Marcantonio D8, Bolton-Gillespie E9, Cramer-Morales K10, Lee J11, Li M12, Slupianek A13, Gritsyuk D14, Cerny-Reiterer S15, Seferynska I16, Stoklosa T17, Bullinger L18, Zhao H19, Gorbunova V20, Piwocka K21, Valent P22, Civin CI23, Muschen M24, Dick JE25, Wang JC26, Bhatia S27, Bhatia R28, Eppert K29, Minden MD30, Sykes SM31, Skorski T32 |
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Abstract Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase-mediated (DNA-PK-mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK-deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1. DNA-PK-deficient quiescent leukemia cells and BRCA/DNA-PK-deficient proliferating leukemia cells were sensitive to PARP1 inhibitors that were administered alone or in combination with current antileukemic drugs. In conclusion, GEMA-guided targeting of PARP1 resulted in dual cellular synthetic lethality in quiescent and proliferating immature leukemia cells, and is thus a potential approach to eradicate leukemia stem and progenitor cells that are responsible for initiation and manifestation of the disease. Further, an analysis of The Cancer Genome Atlas database indicated that this personalized medicine approach could also be applied to treat numerous solid tumors from individual patients. |
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Publikations ID: 28481221 Quelle: öffnen |
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