Protooncogene
T-cell leukemia 1 (TCL1), which is implicated in human
T-cell prolymphocytic leukemia (T-PLL), interacts with Akt and enhances its
kinase activity, functioning as an Akt
kinase co-activator. Two major
isoforms of TCL1 Protooncogenes (TCL1 and TCL1b) are present adjacent to each other on human chromosome 14q.32. In human T-PLL, both TCL1 and TCL1b are activated by
chromosomal translocation. Moreover, TCL1b-transgenic mice have never been created. Therefore, it remains unclear whether TCL1b itself, independent of TCL1, exhibits oncogenicity. In co-immunoprecipitation assays, both ectopic and endogenous TCL1b interacted with Akt. In in vitro Akt
kinase assays, TCL1b enhanced Akt
kinase activity in dose- and time-dependent manners. Bioinformatics approaches utilizing multiregression analysis, cluster analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, Venn diagrams and Gene Ontology (GO) demonstrated that TCL1b showed highly homologous gene-induction signatures similar to Myr-Akt or TCL1. TCL1b exhibited oncogenicity in in vitro colony-transformation assay. Further, two independent lines of β-actin promoter-driven TCL1b-transgenic mice developed
angiosarcoma on the intestinal tract.
Angiosarcoma is a rare form of
cancer in humans with poor prognosis. Using immunohistochemistry, 11 out of 13 human
angiosarcoma samples were positively stained with both anti-TCL1b and anti-phospho-Akt
antibodies. Consistently, in various
cancer tissues, 69 out of 146 samples were positively stained with anti-TCL1b, out of which 46 were positively stained with anti-phospho-Akt
antibodies. Moreover, TCL1b structure-based inhibitor 'TCL1b-Akt-in' inhibited Akt
kinase activity in in vitro
kinase assays and PDGF (
platelet-derived growth factor)-induced Akt
kinase activities-in turn, 'TCL1b-Akt-in' inhibited cellular proliferation of
sarcoma. The current study disclosed TCL1b bears oncogenicity and hence serves as a novel therapeutic target for human neoplastic diseases.