physiomolecular analysis of S100A6 in leukemia with MLL/AF4

• Project/Area Number: 22591051
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Nippon Medical School
• Principal Investigator: INOKUCHI Kouichi 日本医科大学, 医学部, 教授 (10203267)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: MLL/AF4 / S100A6 / TNFα / caspase / IL24 / FLT3ITD / AFF1 / TNF / FLT3-D835I / 達伝子導入マウス

Research Abstract

We showed that MLL-AF4-positive ALL cell lines are resistant to TNF-α. To examine the mechanism of resistance to TNF-α of MLL-AF4-positive leukemia, we focused on S100A6 as a possible factor. Upregulation of S100A6 expression and inhibition of the p53-caspase8-caspase 3 pathway were observed only in MLL-AF4-positive ALL cell lines in the presence of TNF-α. The effect of S100A6 on resistance to TNF-α by inhibition of the p53-caspase8-caspase 3 pathway of MLL-AF4-positive ALL cell lines were also confirmed by analysis using small interfering RNA against S100A6. This pathway was also confirmed in previously established MLL-AF4 transgenic mice. These results suggest that MLL-AF4-positive ALL escapes from TNF-α-mediated apoptosis by upregulation of S100A6 expression, followed by interfering with p53-caspase 8-caspase 3 pathway.

Research Products

• [Journal Article] Mutations of the epigenetics modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia (2013)
  • Author(s): Wakita S, Yamaguchi H, Omori I, Terada K, Ueda T, Manabe E, Kurosawa S, Iida S, Ibaraki T, Sato Y, Todoroki T, Hirakawa T, Ryoutokuji T, Arai K, Kitano T, Mitamura Y, Kosaka F, Dan K, Inokuchi K
  • Journal Title: Leukemia Volume: 27 Pages: 1044-1052
• [Journal Article] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice (2012)
  • Author(s): Tamai H, Miyake K, Yamaguchi H, Takatori M, Dan K, Inokuchi K, Shimada T
  • Journal Title: Blood Volume: 119 Pages: 64-71
• [Journal Article] Disappearance of Both the <I>BCR/ABL1</I> Fusion Gene and the <I>JAK2</I>V617F Mutation with Dasatinib Therapy in a Patient with Imatinib-Resistant Chronic Myelogenous Leukemia (2012)
  • Author(s): Inokuchi K
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 52 Issue: 2 Pages: 145-147
  • DOI: 10.3960/jslrt.52.145
  • NAID: 10031120441
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed
• [Journal Article] AAV-8 vector expressing IL-24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice. (2012)
  • Author(s): Tamai, H.
  • Journal Title: Blood Volume: 119 Issue: 1 Pages: 64-71
  • DOI: 10.1182/blood-2011-05-354050
  • Peer Reviewed
• [Journal Article] RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinaseinhibitors and rapidly evolves clonally by chromosomal translocations (2011)
  • Author(s): Inokuchi K, Wakita S, Hirakawa T, Tamai H, Yokose N, Yamaguchi H, Dan K
  • Journal Title: Int J Hematol Volume: 94 Pages: 255-60
• [Journal Article] Resistance ofMLL-AFF1-positive acute lymphoblastic leukemia to tumor necrosisfactor-alpha is mediated by S100A6 upregulation (2011)
  • Author(s): Tamai H, Miyake K, Yamaguchi H, Takatori M, Dan K, Inokuchi K, Shimada T
  • Journal Title: Blood Cancer Journal Volume: e38 Issue: 11 Pages: 1-7
  • DOI: 10.1038/bcj.2011.37
  • Peer Reviewed
• [Journal Article] Importance of c-kit mutation detection method sensitivity in prognostic analyses of t(8;21)(q22;q22) acute myeloid leukemia (2011)
  • Author(s): Wakita S, Yamaguchi H, Miyake K, Mitamura Y, Kosaka F, Dan K, Inokuchi K
  • Journal Title: Leukemia Volume: 25 Pages: 1423-1432
• [Journal Article] RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinase inhibitors and rapidly evolves clonally by chromosomal translocations (2011)
  • Author(s): Inokuchi K, et al
  • Journal Title: International Journal Hematology Volume: 94 Issue: 3 Pages: 255-260
  • DOI: 10.1007/s12185-011-0910-z
  • NAID: 10029694299
  • Peer Reviewed
• [Journal Article] Activated K-ras protein accelerates human MLL/AF4-induced leukemo-Lymphomogenicity in a transgenic mouse model (2011)
  • Author(s): Tamai K, Inokuchi K, et al
  • Journal Title: Leuekmia Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Seven-year follow-up of patients receiving imatinib for the treatment of Newly diagnosed chronic myelogenous leukemia by the TARGET system (2011)
  • Author(s): Tauchi T, Kizaki M, et al
  • Journal Title: Leukemia Research Volume: 35 Pages: 585-590
  • Peer Reviewed
• [Journal Article] Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma (2010)
  • Author(s): Hirakawa T, Yamaguchi H, Yokose N, Gomi S, Inokuchi K, Dan K
  • Journal Title: Ann Hematol Volume: 89 Pages: 897-904
• [Journal Article] Identification of TINF2 gene mutations in adult Japanese patients With acquired bone marrow failure syndromes (2010)
  • Author(s): Yamaguchi H, Inokuchi K, et al
  • Journal Title: British Journal Haematology Volume: 150 Pages: 725-727
  • Peer Reviewed
• [Journal Article] Multisteppathogenesis of leukemia via the MLL-AF4 chimeric gene/Flt3 gene tyrosine kinase domain (TKD)mutation-related enhancement of S100A6 expression (2009)
  • Author(s): Yamaguchi H, Hanawa H, Uchida N, Inamai M, Sawaguchi K, Mitamura Y, Shimada T, Dan K, Inokuchi K
  • Journal Title: Exp Hematol Volume: 37 Pages: 701-714
• [Presentation] Clinical study of nilotinib in CML-CP patients with imatinib resistance or intolerance. TSSG study (2012)
  • Author(s): Inokuchi k, et al
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Inokuchi K : Inhibition of S100A6 induces GVL effects in MLL/AF4-positive ALL in human-PBMC-SCID mice model (2012)
  • Author(s): Tamai H, Yamaguchi H, Dan K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] The prognostic impact of FLT3 mutations in acute promyelocytic leukemia (2012)
  • Author(s): Hirakawa T, et al
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Analysis of JAK2/MPL mutations and clinical features among myeloproliferative neoplasms in Japan (2012)
  • Author(s): Okabe M, et al
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Inhibition of S100A6 induces GVL effects in MLL/AF4-positive ALL in human-PBMC-SCID mice model. (2012)
  • Author(s): Tamai H
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] Clinical study of nilotinib in CML-CP patients with imatinib resistance or intolerance. TSSG study. (2012)
  • Author(s): Inokuchi K
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] The clinical features and prognostic impact of DNMT3A gene mutation in Japanese patients with de novo AML (2011)
  • Author(s): Ryoutokuji T, et al
  • Organizer: The 53^<th> annual meeting of the American Society of Hematology
  • Place of Presentation: San Diego
• [Presentation] Gene mutations in paired initial presentation and relapse samples from acute myeloid leukemia patients (2011)
  • Author(s): Wakita S, et al
  • Organizer: The 53^<th> annual meeting of the American Society of Hematology
  • Place of Presentation: San Diego
• [Presentation] Telomerase activity is useful for the screening of cryptic and late onset dyskeratosis congenital and evaluation of the treatment response to anabolic steroids for their bone marrow failure (2011)
  • Author(s): Takeuchi J, et al
  • Organizer: The 16^<th> congress ofthe European Hematology Association
  • Place of Presentation: London
• [Presentation] Gene mutation in paired initial presentation and relapse samples from acute myeloid leukemia (2011)
  • Author(s): Wakita H, et al
  • Organizer: The 16^<th> congress of the European Hematology Association
  • Place of Presentation: London
• [Presentation] The clinical features of DNMT3A gene mutation in Japanese patients with de novo AML (2011)
  • Author(s): Ryoutokuji T, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Clinical course and molecular characteristics of RCSD1-ABL1 positive pre-B lymphoblastic leukemia (2011)
  • Author(s): Wakita S, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Activated K-ras protein accelerates human MLL/AF4-induced leukemo-lymphomogenicity in a transgenic mouse model (2010)
  • Author(s): Tamai H, Inokuchi K, et al.
  • Organizer: 第52回アメリカ血液学会
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2010-12-04
• [Presentation] MLL/AF4 positive acute lymphoblastic leukemia has resistance to tumor necrosis factor-alfa caused by up-reguration of S100A6 (2010)
  • Author(s): Tamai H, et al
  • Organizer: The 52&th annual meeting of the American Society of Hematology
  • Place of Presentation: Orlando Florida
• [Presentation] The activated K-RAS protein accelerates human drived-MLL/AF4 induced leukemo-lymphmogenicity in transgenic mice model (2010)
  • Author(s): Tamai H, et al
  • Organizer: The 52^<th> annual meeting of the American Society of Hematology
  • Place of Presentation: Orlando Florida
• [Presentation] C-kit mutation is a significant prognostic factor of t(8;21) AML: Importance of highly sensitive Q-probe method (2010)
  • Author(s): Wakita S, et al
  • Organizer: 15^<th>.European Hematology Association
  • Place of Presentation: Barcelona, Spain
• [Presentation] Establishment and Characterization of A New Lymphoid Malignancy Mouse Model Induced by the combination of MLL/AF4 and K-RAS (2010)
  • Author(s): 玉井勇人
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Gene Therapy of Acute Lymphoblastic Leukemia with MLL/AF4 Using AAV8-IL24 (2010)
  • Author(s): 玉井勇人
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] Establishment of Aggressive MLL/AF4Induced Lymphoma Model Mice ThroughUP-Regulation of HOXA9 and S100A6Expression (2010)
  • Author(s): 玉井勇人
  • Organizer: 第16回日本遺伝子治療学会
  • Place of Presentation: 宇都宮
• [Book] 血液・造血器疾患のマネージメント (2011)
  • Author(s): 猪口孝一、室井一男, 他
  • Total Pages: 219
  • Publisher: 医薬ジャーナル社
• [Patent(Industrial Property Rights)] ヒト MLL/AF4 融合遺伝子導入トランスジェニック非ヒト動物 (2008)
  • Inventor(s): 猪口孝一
  • Industrial Property Rights Holder: 日本医科大学医学部
  • Industrial Property Number: 2008-319606
  • Filing Date: 2008-12-16