Submitted November 6, 2007
Accepted April 1, 2008
Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytes
Mithun Vinod Shah, Ranran Zhang, Rosalyn Irby, Ravi Kothapalli, Xin Liu, Ty Arrington, Bryan Frank, Norman H. Lee, and Thomas P. Loughran Jr.*
Penn State Cancer Institute, Penn State, Hershey, PA, United States
Shriners Hospital for Children, Shriners Hospital for Children, Tampa, FL, United States
Pharmacology & Physiology, George Washington University Medical Center, Washington, DC, United States
* Corresponding author; email: tloughran{at}psu.edu.
T-cell large granular lymphocyte (LGL) leukemia is characterized by clonal expansion of CD3+ CD8+ cells. Leukemic LGL correspond to terminally differentiated effector-memory cytotoxic T-lymphocytes (CTL) that escape Fas-mediated activation-induced cell death (AICD) in vivo. The gene expression signature of peripheral blood mononuclear cells from thirty LGL leukemia patients showed profound dysregulation of expression of apoptotic genes and suggested uncoupling of activation and apoptotic pathways as a mechanism for failure of AICD in leukemic LGL. Pathway based microarray analysis indicated that balance of pro-apoptotic and anti-apoptotic sphingolipid mediated signaling was deregulated in leukemic LGL. We further investigated sphingolipid pathways and found that acid ceramidase was constitutively overexpressed in leukemic LGL and that its inhibition induced apoptosis of leukemic LGL. We also showed that S1P5 is the predominant S1P-receptor in leukemic LGL, while S1P1 is downregulated. FTY720, a functional antagonist of S1P-mediated signaling, induced apoptosis in leukemic LGL and also sensitized leukemic LGL to Fas-mediated death. Collectively, these results show a role for sphingolipid-mediated signaling as a mechanism for long-term survival of CTL. Therapeutic targeting of this pathway, such as use of FTY720, may have efficacy in LGL leukemia.
