JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition
Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression...
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American Society for Clinical Investigation
2018
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| Online Access: | http://hdl.handle.net/1721.1/116943 https://orcid.org/0000-0003-4250-7355 https://orcid.org/0000-0002-6702-4192 |
| _version_ | 1826208497480499200 |
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| author | McKenney, Anna Sophia Somasundara, Amritha Varshini Hanasoge Spitzer, Barbara Intlekofer, Andrew M. Ahn, Jihae Shank, Kaitlyn Rapaport, Franck T. Patel, Minal A. Papalexi, Efthymia Chiu, April Freinkman, Elizaveta Akbay, Esra A. Steadman, Mya Nagaraja, Raj Yen, Katharine Teruya-Feldstein, Julie Wong, Kwok-Kin Rampal, Raajit Levine, Ross L. Lau, Allison N. Shihadeh, Alan Vander Heiden, Matthew G. Thompson, Craig B. Levine, Ross L |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard McKenney, Anna Sophia Somasundara, Amritha Varshini Hanasoge Spitzer, Barbara Intlekofer, Andrew M. Ahn, Jihae Shank, Kaitlyn Rapaport, Franck T. Patel, Minal A. Papalexi, Efthymia Chiu, April Freinkman, Elizaveta Akbay, Esra A. Steadman, Mya Nagaraja, Raj Yen, Katharine Teruya-Feldstein, Julie Wong, Kwok-Kin Rampal, Raajit Levine, Ross L. Lau, Allison N. Shihadeh, Alan Vander Heiden, Matthew G. Thompson, Craig B. Levine, Ross L |
| author_sort | McKenney, Anna Sophia |
| collection | MIT |
| description | Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype. |
| first_indexed | 2024-09-23T14:06:35Z |
| format | Article |
| id | mit-1721.1/116943 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T14:06:35Z |
| publishDate | 2018 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | mit-1721.1/1169432022-10-01T19:15:34Z JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition McKenney, Anna Sophia Somasundara, Amritha Varshini Hanasoge Spitzer, Barbara Intlekofer, Andrew M. Ahn, Jihae Shank, Kaitlyn Rapaport, Franck T. Patel, Minal A. Papalexi, Efthymia Chiu, April Freinkman, Elizaveta Akbay, Esra A. Steadman, Mya Nagaraja, Raj Yen, Katharine Teruya-Feldstein, Julie Wong, Kwok-Kin Rampal, Raajit Levine, Ross L. Lau, Allison N. Shihadeh, Alan Vander Heiden, Matthew G. Thompson, Craig B. Levine, Ross L Broad Institute of MIT and Harvard Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Mechanical Engineering Sloan School of Management Koch Institute for Integrative Cancer Research at MIT Lau, Allison N. Shihadeh, Alan Vander Heiden, Matthew G. Thompson, Craig B. Levine, Ross L Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype. Damon Runyon Cancer Research Foundation (DRG-2241-15) Howard Hughes Medical Institute (Faculty Scholars Award) Stand Up To Cancer National Cancer Institute (U.S.) (P50CA165962) National Cancer Institute (U.S.) (P30CA14051) Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project) Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) Program National Institutes of Health (U.S.) (grant U54OD020355-01) National Institutes of Health (U.S.) (grant NCI R01CA172636) National Institutes of Health (U.S.) (grant R35CA197594) National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747). 2018-07-12T18:13:31Z 2018-07-12T18:13:31Z 2018-04 2018-02 2018-07-11T16:46:07Z Article http://purl.org/eprint/type/JournalArticle 0021-9738 1558-8238 http://hdl.handle.net/1721.1/116943 McKenney, Anna Sophia, Allison N. Lau, Amritha Varshini Hanasoge Somasundara, Barbara Spitzer, Andrew M. Intlekofer, Jihae Ahn, Kaitlyn Shank, et al. “JAK2/IDH-Mutant–driven Myeloproliferative Neoplasm Is Sensitive to Combined Targeted Inhibition.” Journal of Clinical Investigation 128, no. 2 (January 22, 2018): 789–804. https://orcid.org/0000-0003-4250-7355 https://orcid.org/0000-0002-6702-4192 http://dx.doi.org/10.1172/JCI94516 Journal of Clinical Investigation Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/ application/pdf American Society for Clinical Investigation The Journal of Clinical Investigation |
| spellingShingle | McKenney, Anna Sophia Somasundara, Amritha Varshini Hanasoge Spitzer, Barbara Intlekofer, Andrew M. Ahn, Jihae Shank, Kaitlyn Rapaport, Franck T. Patel, Minal A. Papalexi, Efthymia Chiu, April Freinkman, Elizaveta Akbay, Esra A. Steadman, Mya Nagaraja, Raj Yen, Katharine Teruya-Feldstein, Julie Wong, Kwok-Kin Rampal, Raajit Levine, Ross L. Lau, Allison N. Shihadeh, Alan Vander Heiden, Matthew G. Thompson, Craig B. Levine, Ross L JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| title | JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| title_full | JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| title_fullStr | JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| title_full_unstemmed | JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| title_short | JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| title_sort | jak2 idh mutant driven myeloproliferative neoplasm is sensitive to combined targeted inhibition |
| url | http://hdl.handle.net/1721.1/116943 https://orcid.org/0000-0003-4250-7355 https://orcid.org/0000-0002-6702-4192 |
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