TY - JOUR
T1 - Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells
AU - Nieborowska-Skorska, Margaret
AU - Sullivan, Katherine
AU - Dasgupta, Yashodhara
AU - Podszywalow-Bartnicka, Paulina
AU - Hoser, Grazyna
AU - Maifrede, Silvia
AU - Martinez, Esteban
AU - Marcantonio, Daniela Di
AU - Bolton-Gillespie, Elisabeth
AU - Cramer-Morales, Kimberly
AU - Lee, Jaewong
AU - Li, Min
AU - Slupianek, Artur
AU - Gritsyuk, Daniel
AU - Cerny-Reiterer, Sabine
AU - Seferynska, Ilona
AU - Stoklosa, Tomasz
AU - Bullinger, Lars
AU - Zhao, Huaqing
AU - Gorbunova, Vera
AU - Piwocka, Katarzyna
AU - Valent, Peter
AU - Civin, Curt I.
AU - Muschen, Markus
AU - Dick, John E.
AU - Wang, Jean C.Y.
AU - Bhatia, Smita
AU - Bhatia, Ravi
AU - Eppert, Kolja
AU - Minden, Mark D.
AU - Sykes, Stephen M.
AU - Skorski, Tomasz
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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 (DNAPK- 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.
AB - 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 (DNAPK- 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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UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000402620800032&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1172/JCI90825
DO - 10.1172/JCI90825
M3 - Article
C2 - 28481221
SN - 0021-9738
VL - 127
SP - 2392
EP - 2406
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -