%0 Journal Article
%T Involvement of KRAS G12A Mutation in the IL-2-Independent Growth of a Human T-LGL Leukemia Cell Line, PLT-2
%A NAOKI MIZUTANI
%A HIROMI ITO
%A KAZUMI HAGIWARA
%A MISA KOBAYASHI
%J Nagoya Journal of Medical Science
%D 2012
%I Nagoya University
%X 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 ¦Â- and ¦Ã-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.
%K Human LGL leukemia cell lines
%K MOTN-1 and PLT-2
%K IL-2 independent growth
%K Ras/MAP/ERK pathway
%K KRAS G12A mutation
%K Ras activity
%U http://www.med.nagoya-u.ac.jp/medlib/nagoya_j_med_sci/7434/05_Mizutani.pdf