title: Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway.
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.
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Research and Development Service, Hines VA Hospital, Hines, IL, USA.|Department of Molecular Pharmacology and Therapeutics, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Xin
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: You
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Department of Biology, Loyola University Chicago, Chicago, IL, USA.|Department of Molecular/Cellular Physiology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: P
authors.initials: P
authors.lastname: Breslin
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, Shanghai, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Cannova
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Volk
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gutierrez
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ni
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Ng
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Patel
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Department of Medicine, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nand
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Kini
authors.affiliation: Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C119724:AGFG1 protein, human; D028861:Nuclear Pore Complex Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases