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Updated: Mar 13, 2026
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway
J Xin1,2,3, D You1, P Breslin1,4,5
1Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
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.
Insights
Inhibition of RIP1/RIP3 signaling in acute myeloid leukemia (AML) cells reduces SOCS1 and enhances sensitivity to interferon-gamma (IFN-γ). Combining RIP1/RIP3 inactivation with IFN-γ treatment effectively targets AML cells.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Tumor necrosis factor-α (TNF-α)-induced necroptosis via RIP1/RIP3 signaling is a potential treatment for apoptosis-resistant leukemia.
- Acute myeloid leukemia (AML) cells, particularly M4/M5 subtypes, exhibit basal RIP1/RIP3 activation but resist necroptosis.
- TNF-α signaling through RIP1/RIP3 stabilizes SOCS1, a negative regulator of interferon-γ (IFN-γ) signaling.
Purpose of the Study:
- To investigate the role of RIP1/RIP3 signaling in AML cell resistance to necroptosis.
- To explore the therapeutic potential of targeting RIP1/RIP3 signaling in combination with IFN-γ for AML treatment.
Main Methods:
- Utilized pharmacologic and genetic assays to inactivate RIP1/RIP3 signaling in AML cells.
- Assessed SOCS1 protein levels, AML cell differentiation, and sensitivity to IFN-γ.
- Evaluated the combined effect of RIP1/RIP3 inactivation and IFN-γ on AML cell clonogenic capacity and in vivo leukemogenic potential.
Main Results:
- Inactivation of RIP1/RIP3 signaling led to reduced SOCS1 protein levels and partial AML cell differentiation.
- AML cells with inactivated RIP1/RIP3 signaling demonstrated enhanced sensitivity to IFN-γ-induced differentiation.
- Combined RIP1/RIP3 inactivation and IFN-γ treatment significantly reduced the clonogenic capacity of primary AML cells and cell lines.
- This combination therapy diminished the leukemogenic potential of murine AML cells in vivo.
Conclusions:
- Targeting RIP1/RIP3 signaling disrupts SOCS1 stabilization, promoting AML cell differentiation.
- Inhibition of RIP1/RIP3 signaling sensitizes AML cells to IFN-γ, offering a potential therapeutic window.
- Combining RIP1/RIP3 inactivation with IFN-γ represents a promising novel strategy for AML treatment by attenuating cell growth and leukemogenesis.
