Tyrosine kinase inhibitor–induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors

Author:

Maifrede Silvia1,Nieborowska-Skorska Margaret1,Sullivan-Reed Katherine1,Dasgupta Yashodhara1,Podszywalow-Bartnicka Paulina12,Le Bac Viet12,Solecka Martyna1,Lian Zhaorui3,Belyaeva Elizaveta A.4,Nersesyan Alina1,Machnicki Marcin M.5,Toma Monika16,Chatain Nicolas7,Rydzanicz Malgorzata8,Zhao Huaqing9,Jelinek Jaroslav10,Piwocka Katarzyna2,Sliwinski Tomasz6,Stoklosa Tomasz5,Ploski Rafal8,Fischer Thomas11,Sykes Stephen M.12,Koschmieder Steffen7,Bullinger Lars1314,Valent Peter15,Wasik Mariusz A.4,Huang Jian3,Skorski Tomasz1

Affiliation:

1. Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA;

2. Laboratory of Cytometry, Nencki Institute of Experimental Biology, Warsaw, Poland;

3. Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA;

4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA;

5. Department of Immunology, The Medical University of Warsaw, Warsaw, Poland;

6. Laboratory of Medical Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Poland;

7. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany;

8. Department of Medical Genetics, The Medical University of Warsaw, Warsaw, Poland;

9. Department of Clinical Sciences and

10. Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, PA;

11. Department of Hematology and Oncology, Center of Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany;

12. Research Institute of Fox Chase Cancer Center, Immune Cell Development and Host Defense, Philadelphia, PA;

13. Department of Internal Medicine III, University of Ulm, Ulm, Germany;

14. Department of Hematology, Oncology and Tumor Immunology, Campus Virchow Klinikum, Charité-University Medicine, Berlin, Germany; and

15. Department of Internal Medicine I, Division of Hematology and Hemostaseology and Ludwig-Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria

Abstract

Key Points FLT3 inhibitor AC220 caused DNA repair defects and sensitized FLT3(ITD)-positive AML stem and progenitor cells to PARP1 inhibitors. Quiescent and proliferating FLT3(ITD)-positive AML cells were eliminated by the combination of FLT3 and PARP1 inhibitors.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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