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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.
Afiliação
  • Zhang P; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Brinton LT; College of Pharmacy, The Ohio State University, Columbus, OH, USA.
  • Gharghabi M; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Sher S; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Williams K; Department of Outcomes and Translational Sciences, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
  • Cannon M; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Walker JS; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Canfield D; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Beaver L; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Cempre CB; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Phillips H; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Chen X; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Yan P; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Lehman A; Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
  • Scherle P; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Wang M; Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
  • Vaddi K; Prelude Therapeutics, Wilmington, DE, USA.
  • Baiocchi R; Prelude Therapeutics, Wilmington, DE, USA.
  • Wang R; Prelude Therapeutics, Wilmington, DE, USA.
  • Sampath D; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Alinari L; Center for Childhood Cancer and Blood Diseases, Hematology/Oncology and BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
  • Blachly JS; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
  • Lapalombella R; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Sci Adv ; 8(37): eabp9005, 2022 Sep 16.
Article em En | MEDLINE | ID: mdl-36112677
ABSTRACT
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.
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Texto completo: 1 Bases de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Sci Adv Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: Sci Adv Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos