We isolated cDNA clones containing the entire coding region of the putative oncogene AKT2. Sequence analysis and in vitro translation demonstrated that AKT2 encodes a 56-kDa protein with homology to serine/threonine kinases; moreover, this protein contains a Src homology 2-like domain. AKT2 was shown to be amplified and overexpressed in 2 of 8 ovarian carcinoma cell lines and 2 of 15 primary ovarian tumors. AKT2 was mapped to chromosome region 19q13.1-q13.2 by fluorescence in situ hybridization. In the two ovarian carcinoma cell lines exhibiting amplification of AKT2, the amplified sequences were localized within homogeneously staining regions. We conclude that AKT2 belongs to a distinct subfamily of protein-serine/threonine kinases containing Src homology 2-like domains and that alterations of AKT2 may contribute to the pathogenesis of ovarian carcinomas. akt, the protooncogene transduced by the acute transforming retrovirus AKT8 (1, 2), encodes a protein-serine/threonine kinase containing a Src homology 2-like (SH2-like) domain (3). Two putative human cellular homologs, AKTI and AK12, were cloned by screening a human genomic DNA library with a v-akt probe under conditions of reduced stringency (4). Recently, we obtained AKTI clones from a normal human thymus cDNA library by using an AKTI genomic probe. Sequence analysis of portions of AKTI cDNA clones revealed that AKTI is the true human homolog of v-akt and is identical to the recently cloned RAC gene, which has been shown to encode a kinase related to members of the protein kinase C (PKC) family and the cyclic adenosine monophosphate-dependent protein kinase (cAMP-PK) (5). AKTI has been mapped to human chromosome band 14q32 (6), proximal to the immunoglobulin heavy-chain locus, and has been shown to be amplified in a gastric adenocarcinoma (4).In this communication, we report the cDNA cloning, sequence analysis,t and chromosomal mapping ofAKT2 and demonstrate that this putative oncogene encodes a protein belonging to a subfamily of serine/threonine kinases containing SH2-like domains. Moreover, we show that AKT2 is amplified and overexpressed in some human ovarian carcinoma cell lines and primary tumors, suggesting that it contributes to the development of common epithelial tumors of the ovary.

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and achieves a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the anti-tumor effects of imatinib. Imatinib therapy activated CD8+ T cells and induced regulatory T cell (T reg) apoptosis within the tumor by reducing tumor cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are critical to the anti-tumor effects of imatinib in GIST and concomitant immunotherapy may further improve outcome in human cancers treated with targeted agents.

Large intergenic noncoding RNAs (lincRNA) have been less studied than miRNAs in cancer, although both offer considerable theranostic potential. In this study, we identified frequent upregulation of miR-196a and lincRNA HOTAIR in high-risk gastrointestinal stromal tumors (GIST). Overexpression of miR-196a was associated with high-risk grade, metastasis and poor survival among GIST specimens. miR-196a genes are located within the HOX gene clusters and microarray expression analysis revealed that the HOXC and HOTAIR gene were also coordinately upregulated in GISTs which overexpress miR-196a. In like manner, overexpression of HOTAIR was also strongly associated with high-risk grade and metastasis among GIST specimens. RNA interference-mediated knockdown of HOTAIR altered the expression of reported HOTAIR target genes and suppressed GIST cell invasiveness. These findings reveal concurrent overexpression of HOX genes with noncoding RNAs in human cancer in this setting, revealing miR-196a and HOTAIR as potentially useful biomarkers and therapeutic targets in malignant GISTs.