Antiapoptotic function of WT1 in leukemia and development of WT1-targeting molecular targeted therapy

• Project/Area Number: 21591205
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: OJI 大阪大学, 大学院医学系・研究科, 寄附講座教授 (20294100)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: WT1 / leukemogenesis / molecular targeted therapy / apoptosis / antiapoptosis

Research Abstract

The WT1 gene is overexpressed in leukemia and involved in leukemogenesis through its antiapoptotic functions. In the present study, proteomic analysis revealed that a protein which regulates metabolism of cancer cells was dephosphorylated in a leukemia cells with forced expression of WT1 17AA(+) isoform. Moreover, 60aa-long WT1-derived peptide induced apoptosis in leukemia cells. West-western analysis showed that this WT1-derived peptide bound directly to multiple proteins regulating metabolism of cancer cells. Moreover, forced expression of WT1 17AA(+) isoform increased these proteins. These results indicated that WT1 17AA(+) isoform was involved in cancer cell metabolism and the molecular mechanism of these functions of WT1 could be a target of novel molecular targeted therapy for leukemia.

Research Products

• [Journal Article] Low Wilms' tumor gene expression in tumor tissues predicts poor prognosis in patients with non-small-cell lung cancer (2012)
  • Author(s): Hayashi S, Oji Y, Kanai Y, Teramoto T, Kitaichi M, Kawaguchi T, Okada M, Sugiyama H, Matsumura A.
  • Journal Title: Cancer Invest Volume: 30 Pages: 165-71
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22148937
• [Journal Article] CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients (2012)
  • Author(s): Hosen N, Matsuoka Y, Kishida S, Nakata J, Mizutani Y, Hasegawa K, Mugitani A, Ichihara H, Aoyama Y, Nishida S, Tsuboi A, Fujiki F, Tatsumi N, Nakajima H, Hino M, Kimura T, Yata K, Abe M, Oka Y, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Leukemia Volume: (in press) Issue: 9 Pages: 2135-2141
  • DOI: 10.1038/leu.2012.80
  • 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
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22399636
• [Journal Article] Use of(11) C-methionine PET parametric response map for monitoring WT1 immunotherapy response in recurrent malignant glioma (2012)
  • Author(s): Chiba Y, Kinoshita M, Okita Y, Tsuboi A, Isohashi K, Kagawa N, Fujimoto Y, Oji Y, Oka Y, Shimosegawa E, Morita S, Hatazawa J, Sugiyama H, Hashimoto N, Yoshimine T.
  • Journal Title: J Neurosurg Volume: 116 Pages: 835-42
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22242671
• [Journal Article] Enhanced tumor immunity of WT1 peptide vaccination by interferon-βadministration (2012)
  • Author(s): Nakajima H, Oka Y, Tsuboi A, Tatsumi N, Yamamoto Y, Fujiki F, Li Z, Murao A, Morimoto S, Hosen N, Shirakata T, Nishida S, Kawase I, Isaka Y, Oji Y, Sugiyama H.
  • Journal Title: Vaccine Volume: 30 Pages: 722-9
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/22133512
• [Journal Article] Biased usage of T cell receptor β-chain variable region genes of Wilms' tumor gene (WT1)-specific CD8^+ T cells in patients with solid tumors and healthy donors (2012)
  • Author(s): Morimoto S., et al
  • Journal Title: Cancer Science Volume: 103 Issue: 3 Pages: 408-414
  • DOI: 10.1111/j.1349-7006.2011.02163.x
  • Peer Reviewed
• [Journal Article] CD48 as a novel molecular target for antibody therapy in multiple myeloma (2012)
  • Author(s): Hosen N, Ichihara H, Mugitani A, Aoyama Y, Fukuda Y, Kishida S, Matsuoka Y, Nakajima H, Kawakami M, Yamagami T, Fuji S, Tamaki H, Nakao T, Nishida S, Tsuboi A, Iida S, Hino M, Oka Y, Oji Y, Sugiyama H.
  • Journal Title: Br J Haematol Volume: 156 Issue: 2 Pages: 213-24
  • DOI: 10.1111/j.1365-2141.2011.08941.x
• [Journal Article] WT1 peptide vaccination following allogeneic stem cell transplantation in pediatric leukemic patients with high risk for relapse : successful maintenance of durable remission (2012)
  • Author(s): Hashii Y, Sato-Miyashita E, Matsumura R, Kusuki S, Yoshida H, Ohta H, Hosen N, Tsuboi A, Oji Y, Oka Y, Sugiyama H, Ozono K.
  • Journal Title: Leukemia Volume: 26 Issue: 3 Pages: 530-2
  • DOI: 10.1038/leu.2011.226
  • Peer Reviewed
• [Journal Article] Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease (2011)
  • 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: 2011(in press) Issue: 6 Pages: 1410-1413
  • DOI: 10.1038/leu.2011.343
  • Peer Reviewed
• [Journal Article] Low Wilms' tumor gene expression in tumor tissues predicts poor prognosis in patients with non-small-cell lung cancer (2011)
  • Author(s): Hayashi S, et al
  • Journal Title: Cancer Invest Volume: 30 Pages: 165-171
  • Peer Reviewed
• [Journal Article] The role of WT1 gene in neuroblastoma. (2011)
  • Author(s): Wang J
  • Journal Title: J Pediatr Surg Volume: 46 Pages: 326-31
  • Peer Reviewed
• [Journal Article] Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways (2010)
  • Author(s): Sitaram RT, Degerman S, Ljungberg B, Andersson E, Oji Y, Sugiyama H, Roos G, Li A.
  • Journal Title: Br J Cancer Volume: 103 Pages: 1255-62
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20842112
• [Journal Article] A clear correlation between WT1-specific Th response and clinical response in WT1 CTL epitope vaccination (2010)
  • Author(s): Fujiki F, Oka Y, Kawakatsu M, Tsuboi A, Tanaka-Harada Y, Hosen N, Nishida S, Shirakata T, Nakajima H, Tatsumi N, Hashimoto N, Taguchi T, Ueda S, Nonomura N, Takeda Y, Ito T, Myoui A, Izumoto S, Maruno M, Yoshimine T, Noguchi S, Okuyama A, Kawase I, Oji Y,
  • Journal Title: Anticancer Res Volume: 30 Pages: 2247-54
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20651376
• [Journal Article] WT1 peptide vaccine induces reduction in minimal residual disease in an Imatinib-treated CML patient (2010)
  • Author(s): Oji Y, Oka Y, Nishida S, Tsuboi A, Kawakami M, Shirakata T, Takahashi K, Murao A, Nakajima H, Narita M, Takahashi M, Morita S, Sakamoto J, Tanaka T, Kawase I, Hosen N, Sugiyama H.
  • Journal Title: Eur J Haematol Volume: 85(4) Issue: 4 Pages: 358-60
  • DOI: 10.1111/j.1600-0609.2010.01497.x
• [Journal Article] Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination (2010)
  • Author(s): Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries IJ, Price DA, Oji Y, Oka Y, Sugiyama H, B
  • Journal Title: Proc Natl Acad Sci USA Volume: 107 Pages: 13824-9
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922237/?tool=pubmed
• [Journal Article] Sensitive immunohistochemical detection of WT1 protein in tumors with anti-WT1 antibody against WT1 235 peptide (2010)
  • Author(s): Ichinohasama R, Oji Y, Yokoyama H, Takeuchi K, Fujiwara T, Ishizawa K, Taniguchi O, Tsuboi A, Oka Y, Sugiyama H.
  • Journal Title: Cancer Sci Volume: 101 Pages: 1089-92
  • NAID: 10026591723
  • URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1349-7006.2010.01522.x/abstract;jsessionid=8A19D28E675DF64AEAAAC58923BDEE88.d02t03
• [Journal Article] High frequencies of less differentiated and more proliferative WT1-specific CD8+ T cells in bone marrow in tumor-bearing patients : an important role of bone marrow as a secondary lymphoid organ (2010)
  • Author(s): Murao A, Oka Y, Tsuboi A, Elisseeva OA, Tanaka-Harada Y, Fujiki F, Nakajima H, Nishida S, Hosen N, Shirakata T, Hashimoto N, Myoui A, Ueda T, Takeda Y, Osaki T, Enomoto T, Yoshikawa H, Kimura T, Oji Y, Kawase I, Sugiyama H.
  • Journal Title: Cancer Sci Volume: 101 Pages: 848-54
  • NAID: 10026590478
  • URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1349-7006.2009.01468.x/abstract
• [Journal Article] Biased usage of BV gene families of T-cell receptors of WT1(Wilms' tumor gene)-specific CD8+ T cells in patients with myeloid malignancies (2010)
  • Author(s): Tanaka-Harada Y, Kawakami M, Oka Y, Tsuboi A, Katagiri T, Elisseeva OA, Nishida S, Shirakata T, Hosen N, Fujiki F, Murao A, Nakajima H, Oji Y, Kanda Y, Kawase I, Sugiyama H.
  • Journal Title: Cancer Sci Volume: 101 Pages: 594-600
  • NAID: 10026589035
  • URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1349-7006.2009.01453.x/abstract
• [Journal Article] Prognostic significance of WT1 mRNA and anti-WT1 antibody levels inperipheral blood in patients with myelodysplastic syndromes (2010)
  • Author(s): Tamura H, Dan K, Yokose N, Iwakiri R, Ohta M, Sakamaki H, Tohyama K, KondoA, Hyodo H, Nakamura K, Yamashita T, Elisseeva OA, Oka Y, Oji Y, Sugiyama H, Ogata K.
  • Journal Title: Leuk Res Volume: 34 Pages: 986-90
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/20031209
• [Journal Article] Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways. (2010)
  • Author(s): Sitaram RT
  • Journal Title: Br J Cancer Volume: 103 Pages: 1255-62
  • Peer Reviewed
• [Journal Article] Prognostic value of WT1 protein expression level and MIB-1 staining index as predictor of response to WT1 immunotherapy in glioblastoma patients. (2010)
  • Author(s): Chiba Y
  • Journal Title: Brain Tumor Pathol Volume: 27 Pages: 29-34
  • Peer Reviewed
• [Journal Article] WT1 IgG antibody for early detection of nonsmall cell lung cancer and as its prognostic factor (2009)
  • Author(s): Oji Y, et al.
  • Journal Title: Int J Cancer 125 Pages: 381-7
  • Peer Reviewed
• [Presentation] Standardization of WT1 Immunohistochemical Staining and Evaluation of WT1 Positivity in Solid Cancers (2011)
  • Author(s): Oji Y, Berneman Z. N, Keilholz U, O' reilly R, Saglio G, Wagner N, Heike Y, Lundin E, Aozasa K, Pauwels P, Anguille S, Cilloni D, Ohashi H, Waelput W, Fukuda M, Tatsumi N, Oka Y, Sugiyama H.
  • Place of Presentation: Turin, Italy
  • Year and Date: 2011-04-15
• [Presentation] WT1 Expression in Tumor Endothelial Cells (2010)
  • Author(s): Fukuda M, Oji Y, Nakatsuka S, Oka Y, Tsuboi A, Hosen N, Nishida S, Tatsumi N, Aozasa K, Sugiyama K.
  • Organizer: 第69回日本癌学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-24