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Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1.
Coleman, Daniel J L; Keane, Peter; Chin, Paulynn S; Ames, Luke; Kellaway, Sophie; Blair, Helen; Khan, Naeem; Griffin, James; Holmes, Elizabeth; Maytum, Alexander; Potluri, Sandeep; Strate, Lara; Koscielniak, Kinga; Raghavan, Manoj; Bushweller, John; Heidenreich, Olaf; Rabbitts, Terry; Cockerill, Peter N; Bonifer, Constanze.
Afiliación
  • Coleman DJL; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Keane P; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Chin PS; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Ames L; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Kellaway S; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Blair H; Wolfson Childhood Cancer Research Centre, University of Newcastle, Newcastle upon Tyne, UK.
  • Khan N; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
  • Griffin J; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Holmes E; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Maytum A; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Potluri S; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Strate L; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Koscielniak K; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Raghavan M; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Bushweller J; School of Medicine, University of Virginia, Charlottesville, VA, USA.
  • Heidenreich O; Wolfson Childhood Cancer Research Centre, University of Newcastle, Newcastle upon Tyne, UK.
  • Rabbitts T; Princess Máxima Centrum of Pediatric Oncology, Utrecht, the Netherlands.
  • Cockerill PN; Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
  • Bonifer C; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
iScience ; 27(4): 109576, 2024 Apr 19.
Article en En | MEDLINE | ID: mdl-38638836
ABSTRACT
AML is characterized by mutations in genes associated with growth regulation such as internal tandem duplications (ITD) in the receptor kinase FLT3. Inhibitors targeting FLT3 (FLT3i) are being used to treat patients with FLT3-ITD+ but most relapse and become resistant. To elucidate the resistance mechanism, we compared the gene regulatory networks (GRNs) of leukemic cells from patients before and after relapse, which revealed that the GRNs of drug-responsive patients were altered by rewiring their AP-1-RUNX1 axis. Moreover, FLT3i induces the upregulation of signaling genes, and we show that multiple cytokines, including interleukin-3 (IL-3), can overcome FLT3 inhibition and send cells back into cycle. FLT3i leads to loss of AP-1 and RUNX1 chromatin binding, which is counteracted by IL-3. However, cytokine-mediated drug resistance can be overcome by a pan-RAS inhibitor. We show that cytokines instruct AML growth via the transcriptional regulators AP-1 and RUNX1 and that pan-RAS drugs bypass this barrier.
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Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: IScience Año: 2024 Tipo del documento: Article