Oncogenic functions of the WT1 gene in leukemia

• Project/Area Number: 24591395
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: OJI Yusuke 大阪大学, 医学(系)研究科(研究院), 寄附講座教授 (20294100)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: WT1 / oncogene / chemoresistance / DNA repair / ゲノム安定性維持 / 代謝制御 / 分子標的治療法 / 癌遺伝子

Outline of Final Research Achievements

The WT1 gene is overexpressed in leukemia and various types of solid tumors.In the present research project, we elucidated two novel mechanisms by which WT1 exerts its oncogenic functions. First, WT1 induced resistance to chemotherapeutic drugs such as DOX through promotion of homologous recombination (HR) that plays a critical role in DNA damage repair responses. Among four isoforms of WT1, WTC isoform alone promoted HR, which resulted from upregulation of HR factors, XRCC2, Rad51D, and Rad54. Immunohistochemistry showed that XRCC2 and Rad54 proteins were highly expressed in the majority of NSCLC and gastric cancer, and that expression of these two proteins was significantly correlated with that of WT1 protein in NSCLCs. Second, we showed the involvement of cytoplasmic WT1 protein in metabolic regulation through direct binding to metabolic enzymes in tumor cells. These interactions of WT1 with metabolic enzymes might be targets of novel molecular targeted cancer therapy.

Research Products

• [Journal Article] Wilms' tumor gene WT1 promotes homologous recombination- mediated DNA damage repair (2015)
  • Author(s): Oji Y, Kobayashi J, et al.
  • Journal Title: Mol Carcinog Volume: in press Issue: 12 Pages: 1758-71
  • DOI: 10.1002/mc.22248
  • Peer Reviewed / Open Access
• [Journal Article] Transduction of a Novel HLA-DRB1*04:05-restricted, WT1-specific TCR Gene into Human CD4+ T Cells Confers Killing Activity Against Human Leukemia Cells. (2015)
  • Author(s): Katsuhara A, Fujiki F, Aoyama N, Tanii S, Morimoto S, Oka Y, Tsuboi A, Nakajima H, Kondo K, Tatsumi N, Nakata J, Nakae Y, Takashima S, Nishida S, Hosen N, Sogo S, Oji Y, Sugiyama H.
  • Journal Title: Anticancer Res Volume: 35 Pages: 1251-1261
  • Peer Reviewed / Open Access
• [Journal Article] Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response. (2015)
  • Author(s): Hashimoto N, Tsuboi A, Kagawa N, Chiba Y, Izumoto S, Kinoshita M, Kijima N, Oka Y, Morimoto S, Nakajima H, Morita S, Sakamoto J, Nishida S, Hosen N, Oji Y, Arita N, Yoshimine T, Sugiyama H.
  • Journal Title: Cancer Immunol Immunother Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients. (2015)
  • Author(s): Nakae Y, Oka Y, Fujiki F, Morimoto S, Kamiya T, Takashima S, Nakata J, Nishida S, Nakajima H, Hosen N, Tsuboi A, Kyo T, Oji Y, Mizuguchi K, Kumanogoh A, Sugiyama H.
  • Journal Title: Cancer Immunol Immunother Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma. (2014)
  • Author(s): Andersson C, Oji Y, Ohlson N, Wang S, Li X, Ottander U, Lundin E, Sugiyama H, Li A.
  • Journal Title: Cancer Med Volume: 3 Issue: 4 Pages: 909-918
  • DOI: 10.1002/cam4.244
  • Peer Reviewed / Open Access
• [Journal Article] The translation elongation factor eEF2 is a novel tumor-associated antigen overexpressed in various types of cancers. (2014)
  • Author(s): Oji Y, Tatsumni N, Izumoto S (34 名省略）
  • Journal Title: Int J Oncol Volume: 44 Issue: 5 Pages: 1461-1469
  • DOI: 10.3892/ijo.2014.2318
  • Peer Reviewed / Open Access
• [Journal Article] The Wilms' Tumor Gene WT1 - 17AA/- KTS Splice Variant Increases Tumorigenic Activity Through Up-Regulation of Vascular Endothelial Growth Factor in an In Vivo Ovarian Cancer Model. (2014)
  • Author(s): Yamanouchi K, Ohta T, Liu Z, Oji Y, Sugiyama H, Shridhar V, Matsumura S, Takahashi T, Takahashi K, Kurachi H.
  • Journal Title: Transl Oncol Volume: 24 Issue: 5 Pages: 580-589
  • DOI: 10.1016/j.tranon.2014.07.008
  • Peer Reviewed / Open Access
• [Journal Article] Translation elongation factor eEF2 is a novel tumor-associated antigen overexpressed in various types of cancers. (2014)
  • Author(s): Oji Y, Tatsumi N, Fukuda M, Nakatsuka S, Aoyagi S, Hirata E, Nanchi I, Fujiki F, Nakajima H, Yamamoto Y, Shibata S, Nakamura M, Hasegawa K, Takagi S, Fukuda I, Hoshikawa T, Murakami Y, Mori M, Inoue M, Naka T, Tomonaga T, Shimizu Y, Nakagawa M, Hasegawa J, Nezu R, Inohara H, Izumoto S, Nonomura N, Yoshimine T, et al.
  • Journal Title: Int J Oncol. Volume: 44 Pages: 1461-9
  • Peer Reviewed
• [Journal Article] Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma. (2014)
  • Author(s): Andersson C, Oji Y, Ohlson N, Wang S, Li X, Ottander U, Lundin E, Sugiyama H, Li A.
  • Journal Title: Cancer Med. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Wilms' tumor 1 is involved in tumorigenicity of glioblastoma by regulating cell proliferation and apoptosis. (2014)
  • Author(s): Kijima N, Hosen N, Kagawa N, Hashimoto N, Kinoshita M, Oji Y, Sugiyama H, Yoshimine T.
  • Journal Title: Anticancer Res. Volume: 34 Pages: 61-7
  • Peer Reviewed
• [Journal Article] Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. (2014)
  • Author(s): Nishida S, Koido S, Takeda Y, Homma S, Komita H, Takahara A, Morita S, Ito T, Morimoto S, Hara K, Tsuboi A, Oka Y, Yanagisawa S, Toyama Y, Ikegami M, Kitagawa T, Eguchi H, Wada H, Nagano H, Nakata J, Nakae Y, Hosen N, Oji Y, Tanaka T, Kawase I, Kumanogoh A, Sakamoto J, Doki Y, Mori M, Ohkusa T, Tajiri H, Sugiyama H.
  • Journal Title: J Immunother. Volume: 37 Pages: 105-14
  • Peer Reviewed
• [Journal Article] Identification of a Wilms' tumor 1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes. (2013)
  • Author(s): Anguille S, Fujiki F, Smits EL, Oji Y, Lion E, Oka Y, Berneman ZN, Sugiyama H.
  • Journal Title: Leukemia. Volume: 27 Pages: 748-50
  • Peer Reviewed
• [Journal Article] HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells. (2013)
  • Author(s): Lin Y, Fujiki F, Katsuhara A, Oka Y, Tsuboi A, Aoyama N, Tanii S, Nakajima H, Tatsumi N, Morimoto S, Tamanaka T, Tachino S, Hosen N, Nishida S, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: J Immunother. Volume: 36 Pages: 159-70
  • Peer Reviewed
• [Journal Article] Functional human Th17 clones with WT1-specific helper activity. (2013)
  • Author(s): Tachino S, Fujiki F, Oka Y, Tsuboi A, Morimoto S, Lin YH, Tamanaka T, Kondo K, Nakajima H, Nishida S, Hosen N, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Cancer Immunol Immunother. Volume: 62 Pages: 801-10
  • Peer Reviewed
• [Journal Article] In vivo eradication of MLL/ENL leukemia cells by NK cells in the absence of adaptive immunity. (2013)
  • Author(s): Nakata J, Nakano K, Okumura A, Mizutani Y, Kinoshita H, Iwai M, Hasegawa K, Morimoto S, Fujiki F, Tatsumi N, Nakajima H, Nakae Y, Nishida S, Tsuboi A, Oji Y, Oka Y, Sugiyama H, Kumanogoh A, Hosen N.
  • Journal Title: Leukemia. Volume: - Issue: 6 Pages: 1316-1325
  • DOI: 10.1038/leu.2013.374
  • Peer Reviewed
• [Journal Article] Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine (2013)
  • Author(s): Maeda T, Hosen N, Fukushima K, Tsuboi A, Morimoto S, Matsui T, Sata H, Fujita J, Hasegawa K, Nishida S, Nakata J, Nakae Y, Takashima S, Nakajima H, Fujiki F, Tatsumi N, Kondo T, Hino M, Oji Y, Oka Y, Kanakura Y, Kumanogoh A, Sugiyama H
  • Journal Title: Blood Cancer J Volume: 3 Issue: 8 Pages: e130-e130
  • DOI: 10.1038/bcj.2013.29
  • Peer Reviewed
• [Journal Article] WT1 peptide immunotherapy for gynecologic malignancies resistant to conventional therapies: a phase II trial. (2013)
  • Author(s): Miyatake T, Ueda Y, Morimoto A, Enomoto T, Nishida S, Shirakata T, Oka Y, Tsuboi A, Oji Y, Hosen N, Nakatsuka S, Morita S, Sakamoto J, Sugiyama H, Kimura T.
  • Journal Title: J Cancer Res Clin Oncol. Volume: 139 Pages: 457-63
  • Peer Reviewed
• [Journal Article] WT1 peptide therapy for a patient with chemotherapy-resistant salivary gland cancer. (2012)
  • Author(s): Shirakata T, Oka Y, Nishida S, Hosen N, Tsuboi A, Oji Y, Murao A, Tanaka H, Nakatsuka S, Inohara H, Sugiyama H.
  • Journal Title: Anticancer Res Volume: 32 Pages: 1081-5
  • Peer Reviewed
• [Journal Article] Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. (2012)
  • Author(s): Tamanaka T, Oka Y, Fujiki F, Tsuboi A, Katsuhara A, Nakajima H, Hosen N, Nishida S, Lin YH, Tachino S, Akatsuka Y, Kuzushima K, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Anticancer Res Volume: 32 Pages: 5201-9
  • Peer Reviewed
• [Journal Article] Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease. (2012)
  • Author(s): Tsuboi A, Oka Y, Kyo T, Katayama Y, Elisseeva OA, Kawakami M, Nishida S, Morimoto S, Murao A, Nakajima H, Hosen N, Oji Y, Sugiyama H.
  • Journal Title: Leukemia Volume: 26 Pages: 1410-3
  • Peer Reviewed
• [Remarks] 大阪大学免疫造血制御学研究室
  • URL: http://sahswww.med.osaka-u.ac.jp/~hmtonc/index.html
• [Remarks] 大阪大学医学系研究科 免疫造血制御学研究室
  • URL: http://sahswww.med.osaka-u.ac.jp/~hmtonc/index.html