@article{oai:nagoya.repo.nii.ac.jp:00014804,
 author = {MIZUTANI, NAOKI and ITO, HIROMI and HAGIWARA, KAZUMI and KOBAYASHI, MISA and HOSHIKAWA, ASUKA and NISHIDA, YAYOI and TAKAGI, AKIRA and KOJIMA, TETSUHITO and SUZUKI, MOTOSHI and OSAWA, YOSUKE and OHNISHI, KAZUNORI and DAIBATA, MASANORI and MURATE, TAKASHI},
 issue = {3-4},
 journal = {Nagoya Journal of Medical Science},
 month = {Aug},
 note = {Cytokine-dependent cell lines have been used to analyze the cytokine-induced cellular signaling and the mechanism of oncogenesis. In the current study, we analyzed MOTN-1 and PLT-2 cell lines established from different stages of a T-cell large granular lymphocyte leukemia patient (Daibata et al. 2004). MOTN-1 is IL-2-dependent derived from the chronic phase, whereas IL-2-independent PLT-2 is from the aggressive and terminal stage. They shared considerable chromosome abnormalities and the pattern of T-cell receptor rearrangement, presuming that the cytokine independence of PLT-2 was due to the additive genetic abnormality. Besides IL-2, IL-15 supported MOTN-1 cell growth, because these receptors share b- and g-subunits. IL-2 activated ERK, AKT and STAT pathway of MOTN-1. STAT3 pathway of PLT-2 was also activated by IL-2, suggesting intact IL-2 induces signal transduction of PLT-2. However, ERK1/2 but not AKT, was continuously activated in PLT-2, consistent with the increased Ras-activity of PLT-2. Sequence analysis revealed KRAS G12A mutation but not NRAS and HRAS mutation of PLT-2 but not MOTN-1. Another signaling molecule affecting Ras-signaling pathway, SHP2, which has been frequently mutated in juvenile myelomonocytic leukemia (JMML), did not show mutation. Moreover, MEK inhibitor, PD98059, as well as farnesylation inhibitor inhibited PLT-2 cell growth. Using NIH3T3 and MOTN-1, ERK activation, increased cell proliferation and survival by KRAS G12A were shown, suggesting the important role of KRAS G12A in IL-2-independent growth of PLT-2. Taken together, KRAS G12A is important for IL-2-independent growth of PLT-2 cells and suggests the possibility of involvement of KRAS mutation with disease progression.},
 pages = {261--271},
 title = {INVOLVEMENT OF KRAS G12A MUTATION IN THE IL-2-INDEPENDENT GROWTH OF A HUMAN T-LGL LEUKEMIA CELL LINE, PLT-2},
 volume = {74},
 year = {2012}
}