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

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.

• Journal Article Type: Article
• Acceptance Date: Mar 25, 2024
• Online Publication Date: Mar 26, 2024
• Publication Date: Apr 19, 2024
• Deposit Date: May 16, 2024
• Publicly Available Date: May 17, 2024
• Journal: iScience
• Electronic ISSN: 2589-0042
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 27
• Issue: 4
• Article Number: 109576
• DOI: https://doi.org/10.1016/j.isci.2024.109576
• Public URL: https://nottingham-repository.worktribe.com/output/34866880
• Publisher URL: https://www.cell.com/iscience/fulltext/S2589-0042(24)00798-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2589004224007983%3Fshowall%3Dtrue
• Additional Information: This article is maintained by: Elsevier; Article Title: Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1; Journal Title: iScience; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.isci.2024.109576; Content Type: article; Copyright: © 2024 The Author(s). Published by Elsevier Inc.