Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma.
Large homozygous deletions of 9p21 that inactivate CDKN2A, ARF, and MTAP are common in a wide variety of human cancers. The role for CDKN2A and ARF in tumorigenesis is well established, but whether MTAP loss directly affects tumorigenesis is unclear. MTAP encodes the enzyme methylthioadenosine phosphorylase, a key enzyme in the methionine salvage pathway. To determine if loss of MTAP plays a functional role in tumorigenesis, we have created an MTAP-knockout mouse. Mice homozygous for a MTAP null allele (Mtap(lacZ)) have an embryonic lethal phenotype dying around day 8 postconception. Mtap/Mtap(lacZ) heterozygotes are born at Mendelian frequencies and appear indistinguishable from wild-type mice during the first year of life, but they tend to die prematurely with a median survival of 585 days. Autopsies on these animals reveal that they have greatly enlarged spleens, altered thymic histology, and lymphocytic infiltration of their livers, consistent with lymphoma. Immunohistochemical staining and fluorescence-activated cell sorting analysis indicate that these lymphomas are primarily T-cell in origin. Lymphoma-infiltrated tissues tend to have reduced levels of Mtap mRNA and MTAP protein in addition to unaltered levels of methyldeoxycytidine. These studies show that Mtap is a tumor suppressor gene independent of CDKN2A and ARF.
Kadariya
Yuwaraj
Y
Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Yin
Bu
B
Tang
Baiqing
B
Shinton
Susan A
SA
Quinlivan
Eoin P
EP
Hua
Xiang
X
Klein-Szanto
Andres
A
Al-Saleem
Tahseen I
TI
Bassing
Craig H
CH
Hardy
Richard R
RR
Kruger
Warren D
WD
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D016516:CD4-CD8 Ratio; D055028:Comparative Genomic Hybridization; D003841:Deoxycytidine / Q000378:metabolism; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018095:Germ-Line Mutation; D006579:Heterozygote; D006720:Homozygote; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000032:analysis; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
D017252:CD3 Complex; D003841:Deoxycytidine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D017493:Leukocyte Common Antigens