Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

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Item Type:	Article
Title:	Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells
Creators Name:	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, C.I., Muschen, M., Dick, J.E., Wang, J.C., Bhatia, S., Bhatia, R., Eppert, K., Minden, M.D., Sykes, S.M. and Skorski, T.
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.
Keywords:	Antineoplastic Agents, Tumor Cell Line, Cell Proliferation, Neoplastic Cell Transformation, Cricetinae, Double-Stranded DNA Breaks, DNA End-Joining Repair, BRCA1 Genes, BRCA2 Genes, Lethal Genes, abl Genes, Leukemia, Inbred NOD Mice, Knockout Mice, SCID Mice, Mouse Embryonic Stem Cells, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, Transcriptome, Xenograft Model Antitumor Assays, Animals, Mice
Source:	Journal of Clinical Investigation
ISSN:	1558-8238
Publisher:	American Society for Clinical Investigation
Volume:	127
Number:	6
Page Range:	2392-2406
Date:	1 June 2017
Official Publication:	https://doi.org/10.1172/JCI90825
PubMed:	View item in PubMed

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