Downregulation of PUMA underlies resistance to FGFR1 inhibitors in the stem cell leukemia/lymphoma syndrome

Yun Liu, Baohuan Cai, Yating Chong, Hualei Zhang, Chesley Anne Kemp, Sumin Lu, Chang Sheng Chang, Mingqiang Ren, John K. Cowell, Tianxiang Hu

Research output: Contribution to journalArticlepeer-review

Abstract

Resistance to molecular therapies frequently occur due to genetic changes affecting the targeted pathway. In myeloid and lymphoid leukemias/lymphomas resulting from constitutive activation of FGFR1 kinases, resistance has been shown to be due either to mutations in FGFR1 or deletions of PTEN. RNA-Seq analysis of the resistant clones demonstrates expression changes in cell death pathways centering on the p53 upregulated modulator of apoptosis (Puma) protein. Treatment with different tyrosine kinase inhibitors (TKIs) revealed that, in both FGFR1 mutation and Pten deletion-mediated resistance, sustained Akt activation in resistant cells leads to compromised Puma activation, resulting in suppression of TKI-induced apoptosis. This suppression of Puma is achieved as a result of sequestration of inactivated p-Foxo3a in the cytoplasm. CRISPR/Cas9 mediated knockout of Puma in leukemic cells led to an increased drug resistance in the knockout cells demonstrating a direct role in TKI resistance. Since Puma promotes cell death by targeting Bcl2, TKI-resistant cells showed high Bcl2 levels and targeting Bcl2 with Venetoclax (ABT199) led to increased apoptosis in these cells. In vivo treatment of mice xenografted with resistant cells using ABT199 suppressed leukemogenesis and led to prolonged survival. This in-depth survey of the underlying genetic mechanisms of resistance has identified a potential means of treating FGFR1-driven malignancies that are resistant to FGFR1 inhibitors.

Original languageEnglish (US)
Article number884
JournalCell Death and Disease
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2020

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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