The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma.
Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential.
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Elisa
E
Oricchio
Gouri
G
Nanjangud
Andrew L
AL
Wolfe
Jonathan H
JH
Schatz
Konstantinos J
KJ
Mavrakis
Man
M
Jiang
Xiaoping
X
Liu
Joanne
J
Bruno
Adriana
A
Heguy
Adam B
AB
Olshen
Nicholas D
ND
Socci
Julie
J
Teruya-Feldstein
Frances
F
Weis-Garcia
Wayne
W
Tam
Rita
R
Shaknovich
Ari
A
Melnick
Juha P
JP
Himanen
R S K
RS
Chaganti
Hans-Guido
HG
Wendel
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6; D016147:Genes, Tumor Suppressor; D023281:Genomics; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D034622:RNA Interference; D036141:Receptor, EphA7 / Q000378:metabolism*; D000069283:Rituximab; D014183:Transplantation, Heterologous
D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D036141:Receptor, EphA7