EphB receptors trigger Akt activation and suppress Fas receptor-induced apoptosis in malignant T lymphocytes.
Treatment of hematopoietic malignancies often requires allogeneic bone marrow transplantation, and the subsequent graft-versus-leukemia response is crucial for the elimination of malignant cells. Cytotoxic T lymphocytes and NK cells responsible for the immunoelimination express Fas ligand and strongly rely on the induction of Fas receptor-mediated apoptosis for their action. Although cancer cells are removed successfully by graft-versus-leukemia reactions in myeloid malignancies, their efficiency is low in T cell leukemias. This may be partially because of the ability of malignant T cells to escape apoptosis. Our work shows that Eph family receptor EphB3 is consistently expressed by malignant T lymphocytes, most frequently in combination with EphB6, and that stimulation with their common ligands, ephrin-B1 and ephrin-B2, strongly suppresses Fas-induced apoptosis in these cells. This effect is associated with Akt activation and with the inhibition of the Fas receptor-initiated caspase proteolytic cascade. Akt proved to be crucial for the prosurvival response, because inhibition of Akt, but not of other molecules central to T cell biology, including Src kinases, MEK1 and MEK2, blocked the antiapoptotic effect. Overall, this demonstrates a new role for EphB receptors in the protection of malignant T cells from Fas-induced apoptosis through Akt engagement and prevention of caspase activation. Because Fas-triggered apoptosis is actively involved in the graft-versus-leukemia response and cytotoxic T cells express ephrin-Bs, our observations suggest that EphB receptors are likely to support immunoevasivenes of T cell malignancies and may represent promising targets for therapies, aiming to enhance immunoelimination of cancerous T cells.
Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan S4S 0A2, Canada.
Alison
A
Maddigan
Luke
L
Truitt
Ryan
R
Arsenault
Tanya
T
Freywald
Odette
O
Allonby
Jonathan
J
Dean
Aru
A
Narendran
Jim
J
Xiang
Andrew
A
Weng
Scott
S
Napper
Andrew
A
Freywald
D017209:Apoptosis / Q000502:physiology*; D002469:Cell Separation; D004789:Enzyme Activation / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D036081:Receptors, Eph Family / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D019139:Tumor Escape / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism*
D019014:fas Receptor; D036081:Receptors, Eph Family; D051057:Proto-Oncogene Proteins c-akt