Involvement of KRAS G12A mutation in the IL-2-independent growth of a human T-LGL leukemia cell line, PLT-2

Naoki Mizutani, Hiromi Ito, Kazumi Hagiwara, Misa Kobayashi, Asuka Hoshikawa, Yayoi Nishida, Akira Takagi, Tetsuhito Kojima, Motoshi Suzuki, Yosuke Osawa, Kazunori Ohnishi, Masanori Daibata, Takashi Murate

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Abstract

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 β- and γ-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.

Original languageEnglish
Pages (from-to)261-272
Number of pages12
JournalNagoya journal of medical science
Volume74
Issue number3-4
Publication statusPublished - 01-12-2012

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Mizutani, N., Ito, H., Hagiwara, K., Kobayashi, M., Hoshikawa, A., Nishida, Y., Takagi, A., Kojima, T., Suzuki, M., Osawa, Y., Ohnishi, K., Daibata, M., & Murate, T. (2012). Involvement of KRAS G12A mutation in the IL-2-independent growth of a human T-LGL leukemia cell line, PLT-2. Nagoya journal of medical science, 74(3-4), 261-272.