Table 2.

Summary of known dysregulations in LGL leukemia

Pathway	Details	Potential as treatment modality
Fas and FasL and inhibition of activation-induced cell death (AICD)	Leukemic LGLs have elevated Fas-FasL levels in sera and are resistant to Fas-FasL mediated apoptosis AICD. Soluble Fas (FasS) is elevated in patient sera and can block AICD
Interleukin-15 and Platelet-derived growth Factor (Pdgf) signaling	Computational network modeling suggested that constitutive activation of Interleukin-15 (IL-15) and Pdgf are sufficient to reproduce all known dysregulations in LGL leukemia.	Phase I clinical trials targeting IL-15 with a humanized antibody (Mikβ1) does not appear to be an effective treatment.
Map kinase signaling	Constitutively activated Map kinase signaling has been demonstrated as a critical survival mediator in CLPD-NK.	In vitro pharmacologic Erk inhibition using PD098059 led to apoptosis in the NKL cell line.
Pi3k-Akt signaling	Pi3k-Akt signaling is constitutively active in T-LGL leukemia, due to overactive Src family kinases, which leads to inhibition of pro-apoptotic signaling.	In vitro treatment with Pi3K inhibitor LY 294002 significantly inhibited the activity of NFκB and induced apoptosis in patient T-LGL leukemia PBMCs
Sphingolipid rheostat	Imbalance of sphingolipids has been demonstrated in LGL leukemia. Pro-apoptotic ceramide is decreased and anti- apoptotic sphingosine-1- phosphate is elevated (S1P). S1P receptor 5 is over-expressed in leukemic LGLs	In vivo inhibition of acid ceramidase and delivery of C6- ceramide into a rat model of NK-LGL leukemia led to apoptosis of leukemic LGLs. In vitro pharmacological inhibition of Sphingosine kinase 1 via FTY750 led to apoptosis in leukemic LGLs and remission of leukemia in a rat model.
Nuclear-factor κB signaling	Nfκb has been shown to be activated in leukemic LGLs downstream of Akt and promotes the expression of anti- apoptotic Bcl-2 proteins.	Pharmacologic inhibition of NF-κB with BAY 11-7082 in T-LGL cells led to apoptosis in vitro. Bortezomib proteasome inhibitor has shown promise in preclinical studies in T-LGL leukemia cells.
Jak-Stat signaling	Jak-Stat pathway activation has been demonstrated in LGL leukemia. 30–40% of NK and T-LGL patients have somatic activating mutations in the SH2 dimerization and activation domain in the STAT3 gene.	In vitro treatment with Stat3inhibitors in both wildtype and mutant Stat3 patients results in apoptosis in leukemic LGLs. Mutant Stat3 is predictive of an earlier time to treatment failure and may contribute to the auto-immune phenotype in LGL leukemia and related diseases. Y640F Stat3 mutation was predictive of favorable methotrexate response

LGLs = large granular lymphocyte cells; PBMCs = peripheral blood mononuclear cells;