Signaling Pathways Activated by the B-Cell Receptor in Chronic Lymphocytic Leukemia

Maria Teresa Scupoli; Giovanni Pizzolo

Disclosures

Expert Rev Hematol. 2012;5(3):341-348. 

In This Article

PI3K Pathway

Activation of PI3K requires LYN-dependent phosphorylation of CD19, a B cell-specific cell surface molecule expressed during all stages of B-cell ontogeny.[17] Following BCR ligation, the cytoplasmic domain of CD19 can be phosphorylated on multiple tyrosines by LYN, providing binding sites for the p85 adaptor subunit of PI3K and then production of the lipid phosphatidylinositol-3,4,5-triphosphate (PIP3).[18,19] PIP3 recruits several BCR signaling components to the plasma membrane and activates them. The serine/threonine protein kinase AKT is the principal mediator of PI3K, and its activity has direct effects on the apoptosis machinery, for example inactivating the proapoptotic B-cell leukemia/lymphoma 2 (BCL-2)-related protein, BAD, and FOXO fork head transcription factors, which target genes involved in the induction of apoptosis and cell cycle regulation.[20] AKT can also induce the expression of prosurvival genes, apparently by a crosstalk between AKT and NF-κB pathways. Indeed, AKT has been shown to induce the degradation of IκB, thus allowing NF-κB to activate the expression of several anti-apoptotic genes.[21–23] Although probably not a direct AKT substrate, the mammalian target of rapamycin (mTOR) is an important downstream mediator of PI3K-AKT signaling induced by BCR activity. mTOR is a kinase that controls cell growth and proliferation. This function of mTOR is mediated, in part, by its ability to activate serine/threonine kinases of the S6K family, leading to phosphorylation of the S6 ribosomal protein.[24] Moreover, AKT is known to have profound effects on the regulation of cell metabolism and by inhibiting GSK3.[20]

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