Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway

Leukemia. 2017 May;31(5):1154-1165. doi: 10.1038/leu.2016.287. Epub 2016 Oct 17.

Abstract

Tumor necrosis factor-α (TNF-α)-induced RIP1/RIP3 (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3)-mediated necroptosis has been proposed as an alternative strategy for treating apoptosis-resistant leukemia. However, we found that most acute myeloid leukemia (AML) cells, especially M4 and M5 subtypes, produce TNF and show basal level activation of RIP1/RIP3/MLKL signaling, yet do not undergo necroptosis. TNF, through RIP1/RIP3 signaling, prevents degradation of SOCS1, a key negative regulator of interferon-γ (IFN-γ) signaling. Using both pharmacologic and genetic assays, we show here that inactivation of RIP1/RIP3 resulted in reduction of SOCS1 protein levels and partial differentiation of AML cells. AML cells with inactivated RIP1/RIP3 signaling show increased sensitivity to IFN-γ-induced differentiation. RIP1/RIP3 inactivation combined with IFN-γ treatment significantly attenuated the clonogenic capacity of both primary AML cells and AML cell lines. This combination treatment also compromised the leukemogenic ability of murine AML cells in vivo. Our studies suggest that inhibition of RIP1/RIP3-mediated necroptotic signaling might be a novel strategy for the treatment of AML when combined with other differentiation inducers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Differentiation* / drug effects
  • Humans
  • Interferon-gamma / pharmacology
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / pathology*
  • Nuclear Pore Complex Proteins / antagonists & inhibitors
  • Nuclear Pore Complex Proteins / metabolism*
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • AGFG1 protein, human
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases