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Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions
Using a genome-wide CRISPR screen, we identified CDK9, DHODH, and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilterit...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481139/ https://www.ncbi.nlm.nih.gov/pubmed/36112677 http://dx.doi.org/10.1126/sciadv.abp9005 |
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author | Zhang, Pu Brinton, Lindsey T. Gharghabi, Mehdi Sher, Steven Williams, Katie Cannon, Matthew Walker, Janek S. Canfield, Daniel Beaver, Larry Cempre, Casey B. Phillips, Hannah Chen, Xuyong Yan, Pearlly Lehman, Amy Scherle, Peggy Wang, Min Vaddi, Kris Baiocchi, Robert Wang, Ruoning Sampath, Deepa Alinari, Lapo Blachly, James S. Lapalombella, Rosa |
author_facet | Zhang, Pu Brinton, Lindsey T. Gharghabi, Mehdi Sher, Steven Williams, Katie Cannon, Matthew Walker, Janek S. Canfield, Daniel Beaver, Larry Cempre, Casey B. Phillips, Hannah Chen, Xuyong Yan, Pearlly Lehman, Amy Scherle, Peggy Wang, Min Vaddi, Kris Baiocchi, Robert Wang, Ruoning Sampath, Deepa Alinari, Lapo Blachly, James S. Lapalombella, Rosa |
author_sort | Zhang, Pu |
collection | PubMed |
description | Using a genome-wide CRISPR screen, we identified CDK9, DHODH, and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilteritinib sensitivity. The presence of FLT3-ITD is associated with an increase in anaerobic glycolysis, rendering leukemia cells highly sensitive to inhibition of glycolysis. Supportive of this, our data show the enrichment of single guide RNAs targeting 28 glycolysis-related genes upon gilteritinib treatment, suggesting that switching from glycolysis to oxidative phosphorylation (OXPHOS) may represent a metabolic adaption of AML in gilteritinib resistance. CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations. |
format | Online Article Text |
id | pubmed-9481139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94811392022-09-29 Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions Zhang, Pu Brinton, Lindsey T. Gharghabi, Mehdi Sher, Steven Williams, Katie Cannon, Matthew Walker, Janek S. Canfield, Daniel Beaver, Larry Cempre, Casey B. Phillips, Hannah Chen, Xuyong Yan, Pearlly Lehman, Amy Scherle, Peggy Wang, Min Vaddi, Kris Baiocchi, Robert Wang, Ruoning Sampath, Deepa Alinari, Lapo Blachly, James S. Lapalombella, Rosa Sci Adv Biomedicine and Life Sciences Using a genome-wide CRISPR screen, we identified CDK9, DHODH, and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilteritinib sensitivity. The presence of FLT3-ITD is associated with an increase in anaerobic glycolysis, rendering leukemia cells highly sensitive to inhibition of glycolysis. Supportive of this, our data show the enrichment of single guide RNAs targeting 28 glycolysis-related genes upon gilteritinib treatment, suggesting that switching from glycolysis to oxidative phosphorylation (OXPHOS) may represent a metabolic adaption of AML in gilteritinib resistance. CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations. American Association for the Advancement of Science 2022-09-16 /pmc/articles/PMC9481139/ /pubmed/36112677 http://dx.doi.org/10.1126/sciadv.abp9005 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Zhang, Pu Brinton, Lindsey T. Gharghabi, Mehdi Sher, Steven Williams, Katie Cannon, Matthew Walker, Janek S. Canfield, Daniel Beaver, Larry Cempre, Casey B. Phillips, Hannah Chen, Xuyong Yan, Pearlly Lehman, Amy Scherle, Peggy Wang, Min Vaddi, Kris Baiocchi, Robert Wang, Ruoning Sampath, Deepa Alinari, Lapo Blachly, James S. Lapalombella, Rosa Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions |
title | Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions |
title_full | Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions |
title_fullStr | Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions |
title_full_unstemmed | Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions |
title_short | Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor–mediated synergistic antileukemic actions |
title_sort | targeting oxphos de novo purine synthesis as the nexus of flt3 inhibitor–mediated synergistic antileukemic actions |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9481139/ https://www.ncbi.nlm.nih.gov/pubmed/36112677 http://dx.doi.org/10.1126/sciadv.abp9005 |
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