Platelet-Derived Growth Factor (PDGF)-BB Mediates Survival of Leukemic Large Granular Lymphocyte Via An Autocrine Regulatory Pathway

Tumor cells may stimulate their own proliferation through an autocrine mechanism by simultaneously producing growth factors and growth factor receptors. Proto-oncogene Platelet derived growth factor (PDGF) is a multifunctional molecule with roles in cell growth, proliferation, chemotaxis, actin reorganization and apoptosis resistance. PDGF exerts its cellular effects by inducing homo- or hetero-dimeric complex of α- or β-tyrosine kinase receptors, mediating its receptor tyrosine kinase (PDGF-β RTK) auto-phosphorylation, and consequently initiating downstream survival signaling pathway activation cascades. The importance of PDGF ligand and receptor activities in antigenactivated lymphoid malignancies is illustrated by their expression that has only been observed in HTLV-1/2 –immortalized human T lymphocytes, but not in normal T or NK cells. Large granular lymphocyte leukemia (LGL) is similarly defined as an antigen-activated malignancy. Same data suggest that LGL leukemia may be associated with an HTLV–like retrovirus infection. Since the LGL leukemia antigen is postulated to originate from a retroviral immunogen with HTLV-like properties, we investigated the role of PDGF in T- and NK-LGL leukemia. We report that LGL leukemia cells from both T and NK subtypes simultaneously express PDGF-BB and its receptor-β at both mRNA and protein levels. PDGF-BB mediates PDGF-β RTK auto-phosphrylation and consequently initiates downstream survival pathway activation cascade. We observed that PI3 kinase, Src family kinase and their downstream PKB/Akt pathways are constitutively activated in PBMC from LGL leukemia patients. Concurrent inhibition of both PI3 kinase and Src kinase pathways results in an additive effectiveness in induction of apoptosis via inhibition of PKB/Akt and MEK/ERK phosphorylation. In conclusion, PDGF-BB and PDGF receptor-β are highly expressed in LGL leukemia cells. Constitutive expression of PDGF-BB isoform from LGL leukemia cells may possibly be the result of chronic retroviral infection or retroviral antigenic stimulation. Co-expression of PDGF-BB and its receptor-β plays a central role in mediating PDGF/RTK auto-phosphorylation, and its downstream survival pathway activation cascades via an autocrine regulatory mechanism in LGL leukemia.