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

Research output: Contribution to journalArticle

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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
Externally publishedYes

Fingerprint

Large Granular Lymphocytic Leukemia
Interleukin-2
Cell Line
Mutation
Growth
Cytokines
Juvenile Myelomonocytic Leukemia
Prenylation
Interleukin-15
Mitogen-Activated Protein Kinase Kinases
T-Cell Antigen Receptor
Chromosome Aberrations
Sequence Analysis
Disease Progression
Signal Transduction
Cell Survival
Carcinogenesis
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Mizutani, N., Ito, H., Hagiwara, K., Kobayashi, M., Hoshikawa, A., Nishida, Y., ... 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.
Mizutani, Naoki ; Ito, Hiromi ; Hagiwara, Kazumi ; Kobayashi, Misa ; Hoshikawa, Asuka ; Nishida, Yayoi ; Takagi, Akira ; Kojima, Tetsuhito ; Suzuki, Motoshi ; Osawa, Yosuke ; Ohnishi, Kazunori ; Daibata, Masanori ; Murate, Takashi. / Involvement of KRAS G12A mutation in the IL-2-independent growth of a human T-LGL leukemia cell line, PLT-2. In: Nagoya journal of medical science. 2012 ; Vol. 74, No. 3-4. pp. 261-272.
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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.",
author = "Naoki Mizutani and Hiromi Ito and Kazumi Hagiwara and Misa Kobayashi and Asuka Hoshikawa and Yayoi Nishida and Akira Takagi and Tetsuhito Kojima and Motoshi Suzuki and Yosuke Osawa and Kazunori Ohnishi and Masanori Daibata and Takashi Murate",
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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, vol. 74, no. 3-4, pp. 261-272.

Involvement of KRAS G12A mutation in the IL-2-independent growth of a human T-LGL leukemia cell line, PLT-2. / Mizutani, Naoki; Ito, Hiromi; Hagiwara, Kazumi; Kobayashi, Misa; Hoshikawa, Asuka; Nishida, Yayoi; Takagi, Akira; Kojima, Tetsuhito; Suzuki, Motoshi; Osawa, Yosuke; Ohnishi, Kazunori; Daibata, Masanori; Murate, Takashi.

In: Nagoya journal of medical science, Vol. 74, No. 3-4, 01.12.2012, p. 261-272.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Involvement of KRAS G12A mutation in the IL-2-independent growth of a human T-LGL leukemia cell line, PLT-2

AU - Mizutani, Naoki

AU - Ito, Hiromi

AU - Hagiwara, Kazumi

AU - Kobayashi, Misa

AU - Hoshikawa, Asuka

AU - Nishida, Yayoi

AU - Takagi, Akira

AU - Kojima, Tetsuhito

AU - Suzuki, Motoshi

AU - Osawa, Yosuke

AU - Ohnishi, Kazunori

AU - Daibata, Masanori

AU - Murate, Takashi

PY - 2012/12/1

Y1 - 2012/12/1

N2 - 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.

AB - 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.

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Mizutani N, Ito H, Hagiwara K, Kobayashi M, Hoshikawa A, Nishida Y et al. 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. 2012 Dec 1;74(3-4):261-272.