Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes

Abstract

Persistent activation of NF-κB is a prerequisite for development of adult T cell leukemia-lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes a viral transforming protein named Tax, which constitutively activates the canonical IκB kinases (IKK), the central regulator of NF-κB signaling. However, the role of the non-canonical IκB kinases, TBK1 and IKKε, in the pathogenesis of HTLV-1-associated leukemia has not been evaluated. We here show that TBK1/IKKε are crucial pro-survival molecules by maintaining persistent activity of Stat3. Consistent with this finding, silencing Stat3 by the specific shRNA or by the chemical inhibitor ruxolitinib results in drastic impediment of leukemia cell growth. We further find that in HTLV-1-transformed T cells expressing Tax, TBK1 co-localizes with the canonical IκB kinases and Tax in the lipid raft microdomains. The wild type Tax, but not the Tax mutant defective in activating the canonical IKK, promotes the lipid raft translocation of TBK1. This phenomenon correlates with Tax activation of both NF-κB and Stat3. Tax does not interact directly with TBK1/IKKε, and it rather engages a molecular crosstalk between the canonical IKKs and TBK1/IKKε. Our data, therefore, demonstrate a key role of TBK1/IKKε in the survival and proliferation of HTLV-1-transformed T cells and implicate a potential therapy targeting TBK1/IKKε and Stat3 in controlling HTLV-1-mediated oncogenesis.

Decreased RORC expression and downstream signaling in HTLV‐1‐associated adult T‐cell lymphoma/leukemia uncovers an antiproliferative IL17 link: A potential target for immunotherapy?

“…46,47 Immunotherapeutic targeting of Programmed death ligand −1 (PD-L1) can increase Th17 cell count, restoring IL-17A protein levels in naïve T-cells of patients with a loss-of-function STAT3 mutation. [46][47][48] Conversely, inducing Th17 cell differentiation by RORy agonist LYC-54143 simultaneously reduced PD-1 + cell numbers and PD-1 expression in vitro, and resulted in tumor growth inhibition in vivo in two murine models. 49 In ATL, PDL1 gene amplifications have been associated with worse prognosis, especially in aggressive subtypes.…”

Dual TBK1/IKKɛ inhibitor amlexanox attenuates the severity of hepatotoxin‐induced liver fibrosis and biliary fibrosis in mice

“…42 Furthermore, recent studies have shown that NF-κB protects activated HSCs against TNFα-induced apoptosis, 43,44 and inhibition of NF-κB led to the promotion of HSC apoptosis, resulting in reduced severity of liver fibrosis. 42 Furthermore, recent studies have shown that NF-κB protects activated HSCs against TNFα-induced apoptosis, 43,44 and inhibition of NF-κB led to the promotion of HSC apoptosis, resulting in reduced severity of liver fibrosis.…”

Decreased RORC expression and downstream signaling in HTLV-1-associated Adult T-cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy?

“…Studies have suggested that inhibiting the transmembrane protein Programmed death ligand -1 (PD-L1) can increase Th17 cell count. Notably, human anti-PD-L1 antibodies restored IL-17A protein levels in naïve T-cells of patients with a loss-of-function STAT3 mutation [52][53][54] . Also noteworthy is the induction of Th17 cell differentiation by RORy agonist LYC-54143, which simultaneously reduced PD-1 + cell numbers and PD-1 expression in vitro, resulting in tumor growth inhibition in two murine models 55 .…”