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Maner et al. J Cancer Metastasis Treat 2020;6:37 I http://dx.doi.org/10.20517/2394-4722.2020.60 Page 29 of 40
Figure 12. Common pathways in cutaneous T-cell lymphoma. This figure describes the genetic signaling pathway of NOTCH1. NF-κB:
nuclear factor-kappa B; JAK: Janus kinase
Activated JAK is also known to activate PI3K, resulting in eventual activation of AKT [Figure 12] [208] .
Activation of AKT has also been implicated to occur in CTCL through mutations in the PI3K pathway
relating to TCR-CD28 [209] . Additionally, loss of heterozygosity in PTEN, the negative regulator of PI3K, have
[194]
been observed in MF, and PTEN activity is shown to be altered in CTCL . The PI3K pathway is explained
in greater detail in the SCC section of this paper. Activated JAK is also known to activate PI3K, resulting in
eventual activation of AKT [Figure 12] [208] . Activation of AKT has also been implicated to occur in CTCL
through mutations in the PI3K pathway relating to TCR-CD28 [209] .
NF-κB pathway activity has also been shown to be increased in CTCL [206] . The canonical NF-κB pathway
occurs as follows. IkB kinase (IKK) acts to phosphorylate the IkB element of NF-κB-IKB. Phosphorylated
IkB is ubiquitinated, which allows for the degradation of IkB by proteasomes. NF-κB is then able to enter
the nucleus to act as a transcription factor [204] . One of the effects of NF-κB signaling is an upregulation of
its negative regulator IkB. This serves as a negative feedback mechanism of NF-κB signaling [Figure 12] [210] .
The NF-κB pathway is also linked to the activation of AKT. One of the actions of AKT is the
phosphorylation of IKKα, which is part of the IKK complex of the canonical NF-κB pathway [Figure 12].
The non-canonical NF-κB pathway is implicated also in CTCL. Mutations are seen in the C terminal of the
gene NFκB2, which is an area encoding for autoinhibitory functions in NF-κB2. Typically, the C terminal
of inactive NF-κB2 assists in suppressing the canonical NF-κB pathway. Mutations in the NFκB2 gene are,
therefore, thought to contribute to activation of the canonical NF-κB pathway in CTCL [199] .
The genes phospholipase C, gamma 1 (PLGC1), and caspase recruitment domain family member 11
(CARD11) are amplified in CTCL and are thought to contribute to abnormal TCR signaling [199] . PLGC1
activates the NF-κB pathway and nuclear factor of activated T-cells through diacylglycerol and inositol
1,4,5-trisphosphate (IP3), respectively [211] . CARD11 is linked to the induction of the NF-κB pathway,
although the mechanism of action is not yet completely understood [212] .