Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia
Summary: Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we repo...
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doaj-79647199833d47efad6546517c638aa52020-11-25T01:13:26ZengElsevierCell Reports2211-12472018-01-01222350358Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid LeukemiaYan Xiu0Qianze Dong1Qingchang Li2Fengyin Li3Nick Borcherding4Weizhou Zhang5Brendan Boyce6Hai-hui Xue7Chen Zhao8Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, China Medical University, 77 Puhe Rd., Shenbei Xinqu, Shenyang Shi, Liaoning Sheng 110122, ChinaDepartment of Pathology, China Medical University, 77 Puhe Rd., Shenbei Xinqu, Shenyang Shi, Liaoning Sheng 110122, ChinaDepartment of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USADepartment of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Corresponding authorDepartment of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; Corresponding authorSummary: Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option. : Xiu et al. identify a myeloid-leukemia-suppressive role of NIK, which is different from NIK’s tumor-promoting role in lymphoid neoplasms. They show that stabilization of NIK activates non-canonical but represses canonical NF-κB signaling, indicating that NF-κB non-canonical signaling has a role opposite to that of canonical signaling in AML. Keywords: NF-κB, NIK, RelB, RelA, DNMT3A, MEF2C, MLL-AF9, AML, leukemia stem cells, LSCshttp://www.sciencedirect.com/science/article/pii/S221112471731879X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yan Xiu Qianze Dong Qingchang Li Fengyin Li Nick Borcherding Weizhou Zhang Brendan Boyce Hai-hui Xue Chen Zhao |
spellingShingle |
Yan Xiu Qianze Dong Qingchang Li Fengyin Li Nick Borcherding Weizhou Zhang Brendan Boyce Hai-hui Xue Chen Zhao Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia Cell Reports |
author_facet |
Yan Xiu Qianze Dong Qingchang Li Fengyin Li Nick Borcherding Weizhou Zhang Brendan Boyce Hai-hui Xue Chen Zhao |
author_sort |
Yan Xiu |
title |
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia |
title_short |
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia |
title_full |
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia |
title_fullStr |
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia |
title_full_unstemmed |
Stabilization of NF-κB-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia |
title_sort |
stabilization of nf-κb-inducing kinase suppresses mll-af9-induced acute myeloid leukemia |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2018-01-01 |
description |
Summary: Canonical NF-κB signaling is constitutively activated in acute myeloid leukemia (AML) stem cells and is required for maintenance of the self-renewal of leukemia stem cells (LSCs). However, any potential role for NF-κB non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-κB-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-κB non-canonical signaling and represses NF-κB canonical signaling. In addition, stabilization of NIK-induced activation of NF-κB non-canonical signaling upregulates Dnmt3a and downregulates Mef2c, which suppresses and promotes AML development, respectively. Importantly, by querying the connectivity MAP using up- and downregulated genes that are present exclusively in NIK-stabilized LSCs, we discovered that verteporfin has anti-AML effects, suggesting that repurposing verteporfin to target myeloid leukemia is worth testing clinically. Our data provide a scientific rationale for developing small molecules to stabilize NIK specifically in myeloid leukemias as an attractive therapeutic option. : Xiu et al. identify a myeloid-leukemia-suppressive role of NIK, which is different from NIK’s tumor-promoting role in lymphoid neoplasms. They show that stabilization of NIK activates non-canonical but represses canonical NF-κB signaling, indicating that NF-κB non-canonical signaling has a role opposite to that of canonical signaling in AML. Keywords: NF-κB, NIK, RelB, RelA, DNMT3A, MEF2C, MLL-AF9, AML, leukemia stem cells, LSCs |
url |
http://www.sciencedirect.com/science/article/pii/S221112471731879X |
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