The common viral insertion site Evi12 is located in the 5'-noncoding region of Gnn, a novel gene with enhanced expression in two subclasses of human acute myeloid leukemia.
The leukemia and lymphoma disease locus Evi12 was mapped to the noncoding region of a novel gene, Gnn (named for Grp94 neighboring nucleotidase), that is located immediately upstream of the Grp94/Tra1 gene on mouse chromosome 10. The Gnn gene is conserved in mice and humans. Expression of fusion constructs between GFP and Gnn cDNA isoforms in HEK-293 cells showed that Gnn proteins are located mainly in the cytoplasm. Immunoblotting experiments demonstrated the presence of multiple Gnn protein isoforms in most organs, with the lowest levels of expression of the protein detected in bone marrow and spleen. The Evi12-containing leukemia cell line NFS107 showed high levels of expression of a approximately 150-kDa Gnn isoform (Gnn107) that was not observed in control cell lines. Overexpression may be due to the viral insertion in Evi12. The Gnn107 protein is probably encoded by a Gnn cDNA isoform that is expressed exclusively in NFS107 cells and that includes sequences of TU12B1-TY, a putative protein with homology to 5'-nucleotidase enzymes. Interestingly, using Affymetrix gene expression data of a cohort of 285 patients with acute myeloid leukemia (AML), we found that GNN/TU12B1-TY expression was specifically increased in two AML clusters. One cluster consisted of all AML patients with a t(8;21) translocation, and the second cluster consisted of AML patients with a normal karyotype carrying a FLT3 internal tandem duplication. These findings suggest that we identified a novel proto-oncogene that may be causally linked to certain types of human leukemia.
van den Akker
Eric
E
Department of Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. h.vandenakker@erasmusmc.nl
Vankan-Berkhoudt
Yolanda
Y
Valk
Peter J M
PJ
Löwenberg
Bob
B
Delwel
Ruud
R
D020121:5' Untranslated Regions / Q000235:genetics; D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics; D012190:Retroviridae / Q000502:physiology; D016415:Sequence Alignment; D016662:Virus Integration / Q000235:genetics*
D020121:5' Untranslated Regions; D018076:DNA, Complementary; C484021:EVI2A protein, human; C000715470:MAS1 protein, human; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas