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

Local Library Link: Find It @ Loyola

Authors: Xin, J.; You, D.; Breslin, P; Li, J; Zhang, J; Wei, W.; Cannova, J.; Volk, A; Gutierrez, R.; Xiao, Y.; Ni, A.; Ng, G.; Schmidt, R; Xia, Z.; Pan, J.; Chen, H; Patel, M. M.; Kuo, P. C.; Nand, S; Kini, A. R.; Chen, J; Zhu, J.
Article Title: Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway
Abstract: Tumor necrosis factor-alpha (TNF)-induced RIP1/RIP3-mediated necroptosis has been proposed to be 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-gamma (IFN-gamma) 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-gamma-induced differentiation. RIP1/RIP3 inactivation combined with IFN-gamma 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.Leukemia accepted article preview online, 17 October 2016. doi:10.1038/leu.2016.287.
Journal Title: Leukemia
ISSN: 1476-5551; 0887-6924
Publisher: Unknown  
Journal Place: England
Date Published: 2016
Language: ENG
DOI/URL:

10.1038/leu.2016.287
Notes: LR: 20161018; JID: 8704895; 2016/05/10 [received]; 2016/09/27 [revised]; 2016/09/29 [accepted]; aheadofprint