Stabilization of NF-?B-Inducing Kinase Suppresses MLL-AF9-Induced Acute Myeloid Leukemia.

ABSTRACT: Canonical NF-?B 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-?B non-canonical signaling in AML has been largely overlooked. Here, we report that stabilization of NF-?B-inducing kinase (NIK) suppresses AML. Mechanistically, stabilization of NIK activates NF-?B non-canonical signaling and represses NF-?B canonical signaling. In addition, stabilization of NIK-induced activation of NF-?B 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.

SUBMITTER: Xiu Y 

PROVIDER: S-EPMC5810947 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature