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Nieborowska-Skorska M , Sullivan K , Dasgupta Y , Podszywalow-Bartnicka P , Hoser G , Maifrede S , Martinez E , Di Marcantonio D , Bolton-Gillespie E , Cramer-Morales K , Lee J , Li M , Slupianek A , Gritsyuk D , Cerny-Reiterer S , Seferynska I , Stoklosa T , Bullinger L , Zhao H , Gorbunova V , Piwocka K , Valent P , Civin CI , Muschen M , Dick JE , Wang JC , Bhatia S , Bhatia R , Eppert K , Minden MD , Sykes SM , Skorski T
Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells
J Clin Invest. 2017 Jun 01;127(6) :2392-2406
PMID: 28481221 PMCID: PMC5451241 URL: https://www.ncbi.nlm.nih.gov/pubmed/28481221
AbstractQuiescent 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.
NotesNieborowska-Skorska, Margaret Sullivan, Katherine Dasgupta, Yashodhara Podszywalow-Bartnicka, Paulina Hoser, Grazyna Maifrede, Silvia Martinez, Esteban Di Marcantonio, Daniela Bolton-Gillespie, Elisabeth Cramer-Morales, Kimberly Lee, Jaewong Li, Min Slupianek, Artur Gritsyuk, Daniel Cerny-Reiterer, Sabine Seferynska, Ilona Stoklosa, Tomasz Bullinger, Lars Zhao, Huaqing Gorbunova, Vera Piwocka, Katarzyna Valent, Peter Civin, Curt I Muschen, Markus Dick, John E Wang, Jean Cy Bhatia, Smita Bhatia, Ravi Eppert, Kolja Minden, Mark D Sykes, Stephen M Skorski, Tomasz eng P50 CA100632/CA/NCI NIH HHS/ R00 CA158461/CA/NCI NIH HHS/ R01 CA134458/CA/NCI NIH HHS/ R01 CA186238/CA/NCI NIH HHS/ 2017/05/10 06:00 J Clin Invest. 2017 Jun 1;127(6):2392-2406. doi: 10.1172/JCI90825. Epub 2017 May 8.