Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia
As effective therapies for relapse and refractory B-cell acute lymphoblastic leukemia (B-ALL) remain problematic, novel therapeutic strategies are needed. Artemis is a key endonuclease in V(D)J recombination and nonhomologous end joining (NHEJ) of DNA double-strand break (DSB) repair. Inhibition of...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1134121/full |
| _version_ | 1797852830216749056 |
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| author | Heather A. Ogana Samantha Hurwitz Chih-Lin Hsieh Huimin Geng Markus Müschen Deepa Bhojwani Mark A. Wolf James Larocque Michael R. Lieber Yong Mi Kim |
| author_facet | Heather A. Ogana Samantha Hurwitz Chih-Lin Hsieh Huimin Geng Markus Müschen Deepa Bhojwani Mark A. Wolf James Larocque Michael R. Lieber Yong Mi Kim |
| author_sort | Heather A. Ogana |
| collection | DOAJ |
| description | As effective therapies for relapse and refractory B-cell acute lymphoblastic leukemia (B-ALL) remain problematic, novel therapeutic strategies are needed. Artemis is a key endonuclease in V(D)J recombination and nonhomologous end joining (NHEJ) of DNA double-strand break (DSB) repair. Inhibition of Artemis would cause chromosome breaks during maturation of RAG-expressing T- and B-cells. Though this would block generation of new B- and T-cells temporarily, it could be oncologically beneficial for reducing the proliferation of B-ALL and T-ALL cells by causing chromosome breaks in these RAG-expressing tumor cells. Currently, pharmacological inhibition is not available for Artemis. According to gene expression analyses from 207 children with high-risk pre-B acute lymphoblastic leukemias high Artemis expression is correlated with poor outcome. Therefore, we evaluated four compounds (827171, 827032, 826941, and 825226), previously generated from a large Artemis targeted drug screen. A biochemical assay using a purified Artemis:DNA-PKcs complex shows that the Artemis inhibitors 827171, 827032, 826941, 825226 have nanomolar IC50 values for Artemis inhibition. We compared these 4 compounds to a DNA-PK inhibitor (AZD7648) in three patient-derived B-ALL cell lines (LAX56, BLQ5 and LAX7R) and in two mature B-cell lines (3301015 and 5680001) as controls. We found that pharmacological Artemis inhibition substantially decreases proliferation of B-ALL cell lines while normal mature B-cell lines are not markedly affected. Inhibition of DNA-PKcs (which regulates Artemis) using the DNA-PK inhibitor AZD7648 had minor effects on these same primary patient-derived ALL lines, indicating that inhibition of V(D)J hairpin opening requires direct inhibition of Artemis, rather than indirect suppression of the kinase that regulates Artemis. Our data provides a basis for further evaluation of pharmacological Artemis inhibition of proliferation of B- and T-ALL. |
| first_indexed | 2024-04-09T19:39:35Z |
| format | Article |
| id | doaj.art-16124452d48a4bd1a4732545972846eb |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-09T19:39:35Z |
| publishDate | 2023-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-16124452d48a4bd1a4732545972846eb2023-04-04T08:23:46ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-03-011110.3389/fcell.2023.11341211134121Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemiaHeather A. Ogana0Samantha Hurwitz1Chih-Lin Hsieh2Huimin Geng3Markus Müschen4Deepa Bhojwani5Mark A. Wolf6James Larocque7Michael R. Lieber8Yong Mi Kim9Department of Pediatrics, Children’s Hospital Los Angeles, Division of Hematology and Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Pediatrics, Children’s Hospital Los Angeles, Division of Hematology and Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Urology, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Laboratory Medicine, UCSF, San Francisco, CA, United StatesDepartment of Immunobiology, Center of Molecular and Cellular Oncology, Yale University, New Haven, CT, United StatesDepartment of Pediatrics, Children’s Hospital Los Angeles, Division of Hematology and Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesCuria Global Inc, Albany, NY, United StatesCuria Global Inc, Albany, NY, United StatesDepartments of Pathology, The Molecular and Computational Biology Section of the Department of Biological Sciences, USC Norris Comprehensive Cancer Center, Biochemistry and Molecular Biology, Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Pediatrics, Children’s Hospital Los Angeles, Division of Hematology and Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesAs effective therapies for relapse and refractory B-cell acute lymphoblastic leukemia (B-ALL) remain problematic, novel therapeutic strategies are needed. Artemis is a key endonuclease in V(D)J recombination and nonhomologous end joining (NHEJ) of DNA double-strand break (DSB) repair. Inhibition of Artemis would cause chromosome breaks during maturation of RAG-expressing T- and B-cells. Though this would block generation of new B- and T-cells temporarily, it could be oncologically beneficial for reducing the proliferation of B-ALL and T-ALL cells by causing chromosome breaks in these RAG-expressing tumor cells. Currently, pharmacological inhibition is not available for Artemis. According to gene expression analyses from 207 children with high-risk pre-B acute lymphoblastic leukemias high Artemis expression is correlated with poor outcome. Therefore, we evaluated four compounds (827171, 827032, 826941, and 825226), previously generated from a large Artemis targeted drug screen. A biochemical assay using a purified Artemis:DNA-PKcs complex shows that the Artemis inhibitors 827171, 827032, 826941, 825226 have nanomolar IC50 values for Artemis inhibition. We compared these 4 compounds to a DNA-PK inhibitor (AZD7648) in three patient-derived B-ALL cell lines (LAX56, BLQ5 and LAX7R) and in two mature B-cell lines (3301015 and 5680001) as controls. We found that pharmacological Artemis inhibition substantially decreases proliferation of B-ALL cell lines while normal mature B-cell lines are not markedly affected. Inhibition of DNA-PKcs (which regulates Artemis) using the DNA-PK inhibitor AZD7648 had minor effects on these same primary patient-derived ALL lines, indicating that inhibition of V(D)J hairpin opening requires direct inhibition of Artemis, rather than indirect suppression of the kinase that regulates Artemis. Our data provides a basis for further evaluation of pharmacological Artemis inhibition of proliferation of B- and T-ALL.https://www.frontiersin.org/articles/10.3389/fcell.2023.1134121/fullacute lymphoblastic leukemiaARTEMISpharmacological inhibitionproliferationV(D)J recombinationDNA hairpin |
| spellingShingle | Heather A. Ogana Samantha Hurwitz Chih-Lin Hsieh Huimin Geng Markus Müschen Deepa Bhojwani Mark A. Wolf James Larocque Michael R. Lieber Yong Mi Kim Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia Frontiers in Cell and Developmental Biology acute lymphoblastic leukemia ARTEMIS pharmacological inhibition proliferation V(D)J recombination DNA hairpin |
| title | Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia |
| title_full | Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia |
| title_fullStr | Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia |
| title_full_unstemmed | Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia |
| title_short | Artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia |
| title_sort | artemis inhibition as a therapeutic strategy for acute lymphoblastic leukemia |
| topic | acute lymphoblastic leukemia ARTEMIS pharmacological inhibition proliferation V(D)J recombination DNA hairpin |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1134121/full |
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