作者
Pu Zhang, Lindsey T Brinton, Mehdi Gharghabi, Steven Sher, Katie Williams, Matthew Cannon, Janek S Walker, Daniel Canfield, Larry Beaver, Casey B Cempre, Hannah Phillips, Xuyong Chen, Pearlly Yan, Amy Lehman, Peggy Scherle, Min Wang, Kris Vaddi, Robert Baiocchi, Ruoning Wang, Deepa Sampath, Lapo Alinari, James S Blachly, Rosa Lapalombella
发表日期
2022/9/16
期刊
Science advances
卷号
8
期号
37
页码范围
eabp9005
出版商
American Association for the Advancement of Science
简介
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 …
学术搜索中的文章
P Zhang, LT Brinton, M Gharghabi, S Sher, K Williams… - Science Advances, 2022