Figure 6.
Figure 6. Key molecular abnormalities in LGL leukemia. Fas-mediated death-inducing signaling complex (DISC) inhibition: LGL leukemia cells are resistant to Fas-mediated apoptosis. sFas acts as a decoy receptor able to inhibit Fas-dependent apoptosis. Increased level of an inhibitory protein named cellular FADD-like IL-1 converting enzyme inhibitory protein (c-FLIP) contributes to the DISC formation defect. Jak/Stat3 pathway: Stat3 is constitutively activated in LGL leukemia and is responsible for the transcription of B-cell lymphoma 2 and myeloid cell leukemia 1 (Mcl-1) protein expression. Inhibition of Stat3 restores apoptosis of LGL cells whatever the Stat3 mutation status, which implies that Stat3 mutation is not itself mandatory to explain LGL clonal expansion. SOCS3, which inhibits the Jak/Stat3 pathway is significantly decreased in LGL leukemia. Survival signal: LGL leukemia shows a predominant expression of specificity protein 1 (SP1). Sphingosine kinase 1 (SphK1), which converts sphingosine into SP1 is increased in LGL leukemia and SphK1 inhibition leads to leukemic LGLs apoptosis. SP1 binding to SP1R activates a prosurvival signal through extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Moreover, the expression of SP1 receptor, mainly SP1R5, is increased in LGL leukemia. Ras–Raf-1–MEK1-ERK, phosphatidylinositol 3-kinase (PI3K)/AKT pathway are upregulated in LGL leukemia and the inhibition leads to LGL apoptosis. Increased activity of the PI3K-AKT signaling axis is found in T-LGL cells and participate in apoptotic inhibition. NF-κB activity is upregulated in LGL leukemia. NF-κB acts downstream of the PI3K-AKT pathway to prevent apoptosis through Mcl-1 independently of Stat3. A recurrent nonsynonymous mutation in the gene encoding an NF-κB signaling inhibitor, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), was found in 8% of LGL leukemia patients. IL-15 and platelet-derived growth factor (PDGF): IL-15 promotes myc expression through the NF-κB pathway (model of IL-15 transgenic mouse). IL-15 is associated with an increase of global DNA methylation level in LGL leukemia through DNA methyltransferase 3A (DNMT3A) upregulation. The downregulation of microRNA-29 (miR-29) is responsible for the upregulation of DNMT3A, which induce methylation of the tumor suppressor gene Ibd4. GP130, glycoprotein 130; NF-κB, nuclear factor κB; pSTAT3, phosphoSTAT3; SFK, Src family kinase; SP1R5, specificity protein 1 receptor 5.

Key molecular abnormalities in LGL leukemia. Fas-mediated death-inducing signaling complex (DISC) inhibition: LGL leukemia cells are resistant to Fas-mediated apoptosis. sFas acts as a decoy receptor able to inhibit Fas-dependent apoptosis. Increased level of an inhibitory protein named cellular FADD-like IL-1 converting enzyme inhibitory protein (c-FLIP) contributes to the DISC formation defect. Jak/Stat3 pathway: Stat3 is constitutively activated in LGL leukemia and is responsible for the transcription of B-cell lymphoma 2 and myeloid cell leukemia 1 (Mcl-1) protein expression. Inhibition of Stat3 restores apoptosis of LGL cells whatever the Stat3 mutation status, which implies that Stat3 mutation is not itself mandatory to explain LGL clonal expansion. SOCS3, which inhibits the Jak/Stat3 pathway is significantly decreased in LGL leukemia. Survival signal: LGL leukemia shows a predominant expression of specificity protein 1 (SP1). Sphingosine kinase 1 (SphK1), which converts sphingosine into SP1 is increased in LGL leukemia and SphK1 inhibition leads to leukemic LGLs apoptosis. SP1 binding to SP1R activates a prosurvival signal through extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Moreover, the expression of SP1 receptor, mainly SP1R5, is increased in LGL leukemia. Ras–Raf-1–MEK1-ERK, phosphatidylinositol 3-kinase (PI3K)/AKT pathway are upregulated in LGL leukemia and the inhibition leads to LGL apoptosis. Increased activity of the PI3K-AKT signaling axis is found in T-LGL cells and participate in apoptotic inhibition. NF-κB activity is upregulated in LGL leukemia. NF-κB acts downstream of the PI3K-AKT pathway to prevent apoptosis through Mcl-1 independently of Stat3. A recurrent nonsynonymous mutation in the gene encoding an NF-κB signaling inhibitor, tumor necrosis factor alpha-induced protein 3 (TNFAIP3), was found in 8% of LGL leukemia patients. IL-15 and platelet-derived growth factor (PDGF): IL-15 promotes myc expression through the NF-κB pathway (model of IL-15 transgenic mouse). IL-15 is associated with an increase of global DNA methylation level in LGL leukemia through DNA methyltransferase 3A (DNMT3A) upregulation. The downregulation of microRNA-29 (miR-29) is responsible for the upregulation of DNMT3A, which induce methylation of the tumor suppressor gene Ibd4. GP130, glycoprotein 130; NF-κB, nuclear factor κB; pSTAT3, phosphoSTAT3; SFK, Src family kinase; SP1R5, specificity protein 1 receptor 5.

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