Alteration of stress response by a histone methylation abnormality in hematopoietic stem cells

• Project/Area Number: 26860729
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Shiga University of Medical Science (2015); Kyoto University (2014)
• Principal Investigator: KAWAHARA MASAHIRO 滋賀医科大学, 医学部, 助教 (80617449)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 造血分化 / ヒストンメチル化 / 白血病 / 造血幹細胞 / ヒストン脱メチル化酵素 / 血球分化 / DNA損傷ストレス

Outline of Final Research Achievements

In the current study, we focused the hematological function of a histone lysine demethylase, KDM4B, that is reported to be associated with DNA-damage stress and hypoxia stress and is overexpressed in primary acute myeloid leukemia cells. Knockdown or overexpression of KDM4B did not enhance the proliferation capacity nor affect response against DNA-damage stress in leukemmia cells. However, overexpression of KDM4B in hematopoietic stem cells promoted the differentiation towards granulocytes. These data suggest that KDM4B could be involved with myeloid differentiation.

Research Products

• [Journal Article] A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia. (2016)
  • Author(s): 1)Katsurada T, Kawabata H, Kawabata D, Kawahara M, Nakabo Y, Takaori-Kondo A, Yoshida Y.
  • Journal Title: Int J Hematol. Volume: E-pub
  • Peer Reviewed
• [Journal Article] Hypomethylation of the Treg-specific demethylated region in FOXP3 is a hallmark of the regulatory T-cell subtype in adult T-cell leukemia (2016)
  • Author(s): Shimazu Y, Shimazu Y, Hishizawa M, Hamaguchi M, Nagai Y, Sugino N, Fujii S, Kawahara M, Kadowaki N, Nishikawa H, Sakaguchi S, Takaori-Kondo A
  • Journal Title: Cancer Immunol Res Volume: 4 Issue: 2 Pages: 136-145
  • DOI: 10.1158/2326-6066.cir-15-0148
  • Peer Reviewed
• [Journal Article] T memory stem cells are the hierarchical apex of adult T-cell leukemia (2015)
  • Author(s): Nagai Y, Kawahara M, Hishizawa M, Shimazu Y, Sugino N, Fujii S, Kadowaki N, Takaori-Kondo A
  • Journal Title: Blood Volume: 125 Issue: 23 Pages: 3527-3535
  • DOI: 10.1182/blood-2014-10-607465
  • Peer Reviewed
• [Journal Article] T memory stem cells are the hierarchical apex of adult T-cell leukemia (2015)
  • Author(s): Yuya Nagai†, Masahiro Kawahara†, Masakatsu Hishizawa, Yayoi Shimazu, Noriko Sugino, Sumie Fujii, Norimitsu Kadowaki and Akifumi Takaori-Kondo. (†These authors contributed equally to this work.)
  • Journal Title: Blood Volume: in press
  • Peer Reviewed
• [Journal Article] Co-occurrence of monoclonal gammopathy and myelodysplasia: a retrospective study of fourteen cases. (2014)
  • Author(s): 1.Yoshida Y, Oguma S, Ohno H, Nakabo Y, Katsurada T, Kawahara M, Kawabata H.
  • Journal Title: Int J Hematol Volume: 99 Issue: 6 Pages: 721-725
  • DOI: 10.1007/s12185-014-1570-6
  • Peer Reviewed
• [Journal Article] A case of minor BCR-ABL1 positive acute lymphoblastic leukemia following essential thrombocythemia and originating from a clone distinct from that harboring the JAK2-V617F mutation. (2014)
  • Author(s): Nagai Y, Kawahara M, Sugino N, Shimazu Y, Hishizawa M, Yamashita K, Kadowaki N, Takaori-Kondo A
  • Journal Title: Experimental Hematology & Oncology Volume: 3 Issue: 1 Pages: 6-6
  • DOI: 10.1186/2162-3619-3-6
  • NAID: 120005411358
  • Peer Reviewed / Open Access
• [Presentation] Genetic and cytologic analyses about early T cell precursor acute lymphoblastic leukemia (2015)
  • Author(s): Ryusuke Yamamoto, Masahiro Kawahara, Yuya Nagai, Katsuyuki Ohmori, Yayoi Shimazu, Noriko Sugino, Sumie Fujii, Goichi Tatsumi and Akifumi Takaori-Kondo
  • Organizer: 日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Generation of engraftable leukemic stem cells from iPS cells derived from a secondary AML patient (2015)
  • Author(s): Kazuhisa Chonabayashi, Masahiro Kawahara, Masatoshi Nishizawa, Akifumi Takaori-Kondo, Shinya Yamanaka, and Yoshinori Yoshida
  • Organizer: 日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] LSD1 regulates myeloid differentiation via affecting the enhancer activity of GFI1 (2015)
  • Author(s): Noriko Sugino, Masahiro Kawahara, Akinori Kanai, Hirotaka Matsui, Goichi Tatsumi, Ryusuke Yamamoto, Yuya Nagai, Sumie Fujii, Yayoi Shimazu, Masakatsu Hishizawa, Toshiya Inaba, Takayoshi Suzuki, and Akifumi Takaori-Kondo
  • Organizer: 日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] The hierarchy in adult T-cell leukemia that originates from T memory stem cells (2015)
  • Author(s): Yuya Nagai, Masahiro Kawahara, Masakatsu Hishizawa, Yayoi Shimazu, Noriko Sugino, Sumie Fujii, Ryusuke Yamamoto, Goichi Tatsumi, Norimitsu Kadowaki, Akifumi Takaori-Kondo
  • Organizer: 日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Hypomethylation of the TSDR is a hallmark of the Treg subtype in adult T-cell leukemia (2015)
  • Author(s): Yayoi Shimazu, Yutaka Shimazu, Masakatsu Hishizawa, Masahide Hamaguchi, Yuya Nagai, Noriko Sugino, Sumie Fujii, Masahiro Kawahara, Norimitsu Kadowaki, Hiroyoshi Nishikawa, Shimon Sakaguchi, Akifumi Takaori-Kondo
  • Organizer: 日本血液学会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-16
• [Presentation] Patient-specific induced pluripotent stem cells recapitulate the maturation defect of myelodysplastic syndromes. (2014)
  • Author(s): Kazuhisa Chonabayashi, Masahiro Kawahara, Keisuke Okita, Masatoshi Nishizawa,Norimitsu Kadowaki, Akifumi Takaori -Kondo, Shinya Yamanaka, and YoshinoriYoshida.
  • Organizer: The 56th ASH Annual Meeting andExposition
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] The Pharmacological Inhibition of KDM1A Displays Preclinical Efficacy in AML/MDS by Inducing Myelomonocytic Differentiation. (2014)
  • Author(s): Noriko Sugino, Masahiro Kawahara, Takayoshi Suzuki, Yuya Nagai, Yayoi Shimazu, Sumie Fujii, Masakatsu Hishizawa,and Akifumi Takaori-Kondo.
  • Organizer: The 56th ASH Annual Meeting andExposition
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] KDM1A is a promising therapeutic target of myelodysplastic syndromes. (2014)
  • Author(s): Noriko Sugino, Masahiro Kawahara, Takayoshi Suzuki, Sumie Fujii, Yuya Nagai,Yayoi Shimazu, Masakatsu Hishizawa, and Akifumi Takaori-Kondo.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] iPS technology revealed the genetic and functional diversity present in a single MDS patient. (2014)
  • Author(s): Kazuhisa Chonabayashi, Masahiro Kawahara, Keisuke Okita, Masatoshi Nishizawa,Norimitsu Kadowaki, Akifumi Takaori-Kondo, Shinya Yamanaka, and YoshinoriYoshida.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Remarks] 京都大学大学院医学研究科 血液・腫瘍内科学
  • URL: http://www.kuhp.kyoto-u.ac.jp/~hemonc/research/leukemia.html