Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia

Hiroyuki Nakayama, Fumihiko Ishimaru, Nicole Avitahl, Nobuo Sezaki, Nobuharu Fujii, Koichi Nakase, Yoshifumi Ninomiya, Akira Harashima, Jun Minowada, Junjiro Tsuchiyama, Kenji Imajoh, Teruhiko Tsubota, Shunnichi Fukuda, Tatsuo Sezaki, Kensuke Kojima, Masamichi Hara, Hidetaka Takimoto, Seiichi Yorimitsu, Isao Takahashi, Akira MiyataShuichi Taniguchi, Yasunobu Tokunaga, Hisashi Gondo, Yoshiyuki Niho, Shinji Nakao, Taiichi Kyo, Hiroo Dohy, Nanao Kamada, Mine Harada

Research output: Contribution to journalArticle

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Abstract

Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the Ikaros gene as a tumor suppressor gene in mice. This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies. Reverse transcription-PCR was used to determine the relative expression levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lines and human bone marrow samples from patients with hematological malignancies. Among the cell lines examined, only BV-173, which was derived from a chronic myelogenous leukemia (CML) patient in lymphoid blast crisis, overexpressed the dominant-negative isoform, Ik-6. In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hematological malignancies. In some cases, overexpression of the dominant-negative Ik-6 protein was confirmed by Western blot analysis, and Southern blot analysis indicated that decreases in Ikaros activity correlated with a mutation in the Ikaros locus. In summary, these findings suggest that a reduction of Ikaros activity may be an important step in the development of blast crisis in CML and provide further evidence that mutations that alter Ikaros expression may contribute to human hematological malignancies.

Original languageEnglish
Pages (from-to)3931-3934
Number of pages4
JournalCancer Research
Volume59
Issue number16
Publication statusPublished - Aug 15 1999
Externally publishedYes

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Blast Crisis
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hematologic Neoplasms
Protein Isoforms
Mutation
Leukemia, Myeloid, Chronic Phase
T-Lymphocytes
Cell Line
Gene Targeting
Southern Blotting
Tumor Suppressor Genes
Reverse Transcription
Lymphoma
Leukemia
Bone Marrow
Western Blotting
Polymerase Chain Reaction
Messenger RNA
Genes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Nakayama, H., Ishimaru, F., Avitahl, N., Sezaki, N., Fujii, N., Nakase, K., ... Harada, M. (1999). Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Cancer Research, 59(16), 3931-3934.

Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. / Nakayama, Hiroyuki; Ishimaru, Fumihiko; Avitahl, Nicole; Sezaki, Nobuo; Fujii, Nobuharu; Nakase, Koichi; Ninomiya, Yoshifumi; Harashima, Akira; Minowada, Jun; Tsuchiyama, Junjiro; Imajoh, Kenji; Tsubota, Teruhiko; Fukuda, Shunnichi; Sezaki, Tatsuo; Kojima, Kensuke; Hara, Masamichi; Takimoto, Hidetaka; Yorimitsu, Seiichi; Takahashi, Isao; Miyata, Akira; Taniguchi, Shuichi; Tokunaga, Yasunobu; Gondo, Hisashi; Niho, Yoshiyuki; Nakao, Shinji; Kyo, Taiichi; Dohy, Hiroo; Kamada, Nanao; Harada, Mine.

In: Cancer Research, Vol. 59, No. 16, 15.08.1999, p. 3931-3934.

Research output: Contribution to journalArticle

Nakayama, H, Ishimaru, F, Avitahl, N, Sezaki, N, Fujii, N, Nakase, K, Ninomiya, Y, Harashima, A, Minowada, J, Tsuchiyama, J, Imajoh, K, Tsubota, T, Fukuda, S, Sezaki, T, Kojima, K, Hara, M, Takimoto, H, Yorimitsu, S, Takahashi, I, Miyata, A, Taniguchi, S, Tokunaga, Y, Gondo, H, Niho, Y, Nakao, S, Kyo, T, Dohy, H, Kamada, N & Harada, M 1999, 'Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia', Cancer Research, vol. 59, no. 16, pp. 3931-3934.
Nakayama H, Ishimaru F, Avitahl N, Sezaki N, Fujii N, Nakase K et al. Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Cancer Research. 1999 Aug 15;59(16):3931-3934.
Nakayama, Hiroyuki ; Ishimaru, Fumihiko ; Avitahl, Nicole ; Sezaki, Nobuo ; Fujii, Nobuharu ; Nakase, Koichi ; Ninomiya, Yoshifumi ; Harashima, Akira ; Minowada, Jun ; Tsuchiyama, Junjiro ; Imajoh, Kenji ; Tsubota, Teruhiko ; Fukuda, Shunnichi ; Sezaki, Tatsuo ; Kojima, Kensuke ; Hara, Masamichi ; Takimoto, Hidetaka ; Yorimitsu, Seiichi ; Takahashi, Isao ; Miyata, Akira ; Taniguchi, Shuichi ; Tokunaga, Yasunobu ; Gondo, Hisashi ; Niho, Yoshiyuki ; Nakao, Shinji ; Kyo, Taiichi ; Dohy, Hiroo ; Kamada, Nanao ; Harada, Mine. / Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. In: Cancer Research. 1999 ; Vol. 59, No. 16. pp. 3931-3934.
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abstract = "Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the Ikaros gene as a tumor suppressor gene in mice. This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies. Reverse transcription-PCR was used to determine the relative expression levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lines and human bone marrow samples from patients with hematological malignancies. Among the cell lines examined, only BV-173, which was derived from a chronic myelogenous leukemia (CML) patient in lymphoid blast crisis, overexpressed the dominant-negative isoform, Ik-6. In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hematological malignancies. In some cases, overexpression of the dominant-negative Ik-6 protein was confirmed by Western blot analysis, and Southern blot analysis indicated that decreases in Ikaros activity correlated with a mutation in the Ikaros locus. In summary, these findings suggest that a reduction of Ikaros activity may be an important step in the development of blast crisis in CML and provide further evidence that mutations that alter Ikaros expression may contribute to human hematological malignancies.",
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AU - Nakayama, Hiroyuki

AU - Ishimaru, Fumihiko

AU - Avitahl, Nicole

AU - Sezaki, Nobuo

AU - Fujii, Nobuharu

AU - Nakase, Koichi

AU - Ninomiya, Yoshifumi

AU - Harashima, Akira

AU - Minowada, Jun

AU - Tsuchiyama, Junjiro

AU - Imajoh, Kenji

AU - Tsubota, Teruhiko

AU - Fukuda, Shunnichi

AU - Sezaki, Tatsuo

AU - Kojima, Kensuke

AU - Hara, Masamichi

AU - Takimoto, Hidetaka

AU - Yorimitsu, Seiichi

AU - Takahashi, Isao

AU - Miyata, Akira

AU - Taniguchi, Shuichi

AU - Tokunaga, Yasunobu

AU - Gondo, Hisashi

AU - Niho, Yoshiyuki

AU - Nakao, Shinji

AU - Kyo, Taiichi

AU - Dohy, Hiroo

AU - Kamada, Nanao

AU - Harada, Mine

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