Targeting NF-κB–dependent alkaliptosis for the treatment of venetoclax-resistant acute myeloid leukemia cells

Shan Zhu, Jiao Liu, Rui Kang, Minghua Yang, Daolin Tang

Research output: Contribution to journalArticlepeer-review

Abstract

Venetoclax is a highly selective BCL2 inhibitor widely used in the treatment of leukemia, especially chronic lymphocytic leukemia and acute myeloid leukemia (AML). However, long-term use of venetoclax may lead to secondary drug resistance, which constitutes an important obstacle to prolonging the duration of the therapeutic response. Here, we show that the acquired resistance to venetoclax in human AML cell lines depends on NF-κB activation rather than on the upregulation of anti-apoptotic BCL2L1 expression. Moreover, alkaliptosis induced by the small molecular compound JTC801, but not necroptosis and ferroptosis, inhibits the growth of venetoclax-resistant AML cells in vitro and in xenograft mouse models. Mechanistically, NF-κB–mediated CA9 downregulation is required for intracellular pH upregulation, thereby inducing alkaliptosis in venetoclax-resistant cells. These findings provide a new strategy to selectively remove venetoclax-resistant AML cells.

Original languageEnglish (US)
Pages (from-to)55-61
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume562
DOIs
StatePublished - Jul 12 2021

Keywords

  • Acute myeloid leukemia
  • Alkaliptosis
  • BCL2
  • Drug resistance
  • Venetoclax

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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