Identification and regulation mechanism of enhancers for hematopoietic cell fate decision

• Project/Area Number: 16K09846
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Kawahara Masahiro 滋賀医科大学, 医学部, 助教 (80617449)
• Research Collaborator: Tatsumi Goichi ; Asai Ai
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 白血病 / 造血分化 / エンハンサー / ヒストン修飾 / LSD1 / 転写因子

Outline of Final Research Achievements

In the current study, we found that several enhancers which regulate transcription factors involved in hematopoiesis are suppressed in leukemia cells. The interaction between transcription factors and a histone modifier LSD1 is indispensable in suppression of the enhancers. Disruption of the interaction caused the induction of myeloid differentiation in leukemia cells. However, the myeloid differentiation was impaired by knockout of the enhancers. Collectively, the interaction between transcription factors and LSD1 on the enhancers plays an important role in the sustenance of leukemia.

Academic Significance and Societal Importance of the Research Achievements

白血病は、蛋白をコードする遺伝子の変異の積み重ねによって生じ、そうした変異を標的とした新規薬剤の開発が近年進められている。しかし我々の研究は、エンハンサーと呼ばれる遺伝子本体の外側にあるゲノム領域が異常に制御されると、遺伝子発現プログラムが変化し、白血病の維持に関わるらしいことを明らかにした。そして、エンハンサーを抑制するメカニズムが、白血病治療の新たな標的となりうることを明らかにした。

Research Products

• [Journal Article] Astaxanthin, a xanthophyll carotenoid, prevents development of dextran sulphate sodium-induced murine colitis (2019)
  • Author(s): Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Andoh A.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 64 Issue: 1 Pages: 66-72
  • DOI: 10.3164/jcbn.18-47
  • NAID: 130007542255
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] pH-Dependent 5-Aminosalicylates Releasing Preparations Do Not Affect Thiopurine Metabolism (2019)
  • Author(s): Takahashi Kenichiro、Bamba Shigeki、Morita Yasuhiro、Nishida Atsushi、Kawahara Masahiro、Inatomi Osamu、Sugimoto Mitsushige、Sasaki Masaya、Andoh Akira
  • Journal Title: Digestion Volume: 2 Issue: 4 Pages: 1-9
  • DOI: 10.1159/000495690
  • Peer Reviewed
• [Journal Article] Characterization of fungal dysbiosis in Japanese patients with inflammatory bowel disease. (2019)
  • Author(s): Imai T, Inoue R, Kawada Y, Morita Y, Inatomi O, Nishida A, Bamba S, Kawahara M, Andoh A.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 2 Pages: 149-159
  • DOI: 10.1007/s00535-018-1530-7
  • Peer Reviewed
• [Journal Article] Ameliorating effects of bortezomib, a proteasome inhibitor, on development of dextran sulfate sodium-induced murine colitis (2018)
  • Author(s): Sakai S, Nishida A, Ohno M, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Andoh A.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 63 Issue: 3 Pages: 217-223
  • DOI: 10.3164/jcbn.18-42
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Magnified single-balloon enteroscopy in the diagnosis of intestinal follicular lymphoma: a case series. (2018)
  • Author(s): Takahashi K, Bamba S, Kawahara M, Nishida A, Inatomi O, Sasaki M, Tsujikawa T, Kushima R, Sugimoto M, Kitoh K, Andoh A.
  • Journal Title: Intest Res. Volume: 16 Issue: 4 Pages: 628-634
  • DOI: 10.5217/ir.2018.00003
  • Peer Reviewed
• [Journal Article] A novel mutation causing type 1 Gaucher disease found in a Japanese patient with gastric cancer: A case report. (2018)
  • Author(s): Hosoba S, Kito K, Teramoto Y, Adachi K, Nakanishi R, Asai A, Iwasa M, Nishimura R, Moritani S, Kawahara M, Minamiguchi H, Nanba E, Kushima R, Andoh A.
  • Journal Title: Medicine (Baltimore) Volume: 97 Issue: 27 Pages: e11361-e11361
  • DOI: 10.1097/md.0000000000011361
  • Peer Reviewed
• [Journal Article] Effect of fermented vegetable beverage containing Pediococcus pentosaceus in patients with mild to moderate ulcerative colitis. (2018)
  • Author(s): Bamba S, Takahashi K, Imaeda H, Nishida A, Kawahara M, Inatomi O, Sugimoto M, Sasaki M, Andoh A.
  • Journal Title: Biomed Rep. Volume: 9 Pages: 74-80
  • DOI: 10.3892/br.2018.1099
  • Peer Reviewed
• [Journal Article] MicroRNA-33 regulates the population of peripheral inflammatory Ly6Chigh monocytes through dual pathways. (2018)
  • Author(s): Baba O, Horie T, Hakuno D, Nakashima Y, Nishi H, Kuwabara Y, Nakao T, Nishiga M, Nishino T, Ide Y, Nakazeki F, Koyama S, Kimura M, Hanada R, Kawahara M, Kimura T, and Ono K.
  • Journal Title: Mol Cell Biol. Volume: 38 Issue: 14 Pages: 1-17
  • DOI: 10.1128/mcb.00604-17
  • Peer Reviewed / Open Access
• [Journal Article] Selective dissociation between LSD1 and GFI1B by a LSD1 inhibitor NCD38 induces the activation of ERG super-enhancer in erythroleukemia cells. (2018)
  • Author(s): Yamamoto R, Kawahara M, Ito S, Satoh J, Tatsumi G, Hishizawa M, Suzuki T, Andoh A.
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 30 Pages: 21007-21021
  • DOI: 10.18632/oncotarget.24774
  • Peer Reviewed / Open Access
• [Journal Article] 初診時脳内出血を伴う急性骨髄性白血病の中枢神経病変管理における髄液細胞数モニタリングの有用性. (2018)
  • Author(s): 河原 真大, 寺本 由加子, 浅井 愛, 永井 詩穂, 岩佐 磨佐紀, 藤城 綾, 西村 理恵, 南口 仁志, 辻 篤司, 木藤 克之, 安藤 朗.
  • Journal Title: 臨床血液 Volume: 59 Pages: 2578-2582
  • NAID: 130007554686
  • Peer Reviewed
• [Journal Article] Analysis of endoscopic brush samples identified mucosa-associated dysbiosis in inflammatory bowel disease. (2018)
  • Author(s): Nishino K, Nishida A, Inoue R, Kawada Y, Ohno M, Sakai S, Inatomi O, Bamba S, Sugimoto M, Kawahara M, Naito Y, Andoh A
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 1 Pages: 95-106
  • DOI: 10.1007/s00535-017-1384-4
  • Peer Reviewed
• [Journal Article] Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease. (2017)
  • Author(s): Kusaka S, Nishida A, Takahashi K, Bamba S, Yasui H, Kawahara M, Inatomi O, Sugimoto M, Andoh A
  • Journal Title: Clin Exp Immunol. Volume: 191 Issue: 1 Pages: 96-106
  • DOI: 10.1111/cei.13047
  • Peer Reviewed
• [Journal Article] Nanoparticle curcumin ameliorates experimental colitis via modulation of gut microbiota and induction of regulatory T cells. (2017)
  • Author(s): Ohno M, Nishida A, Sugitani Y, Nishino K, Inatomi O, Sugimoto M, Kawahara M, Andoh A
  • Journal Title: PLoS One Volume: 12 Issue: 10 Pages: e0185999-e0185999
  • DOI: 10.1371/journal.pone.0185999
  • Peer Reviewed / Open Access
• [Journal Article] Expression of Interleukin-26 is upregulated in inflammatory bowel disease. (2017)
  • Author(s): Fujii M, Nishida A, Imaeda H, Ohno M, Nishino K, Sakai S, Inatomi O, Bamba S, Kawahara M, Shimizu T, Andoh A
  • Journal Title: World J Gastroenterol. Volume: 23 Issue: 30 Pages: 5519-5529
  • DOI: 10.3748/wjg.v23.i30.5519
  • Peer Reviewed / Open Access
• [Journal Article] Central nervous system involvement of acute promyelocytic leukemia, three case reports (2017)
  • Author(s): Aya Furuya, Masahiro Kawahara*, Mina Kumode, Yasuyuki Ohira, Asako Usui, Shiho Nagai, Sakura Hosoba, Hitoshi Minamiguchi, Katsuyuki Kito & Akira Andoh (* correspondence)
  • Journal Title: Clinical Case Reports Volume: 印刷中 Issue: 5 Pages: 645-653
  • DOI: 10.1002/ccr3.919
  • Peer Reviewed / Open Access
• [Journal Article] A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. (2017)
  • Author(s): Sugino N, Kawahara M, Tatsumi G, Kanai A, Matsui H, Yamamoto R, Nagai Y, Fujii S, Shimazu Y, Hishizawa M, Inaba T, Andoh A, Suzuki T, Takaori-Kondo A.
  • Journal Title: Leukemia Volume: in press Issue: 11 Pages: 2303-2314
  • DOI: 10.1038/leu.2017.59
  • 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
• [Presentation] Mogamulizumab and radiation therapy in two patients with relapsed mature T-cell neoplasm after related PBSCT. (2019)
  • Author(s): Yukako Teramoto, Wataru Saika, Ai Asai, Masaki Iwasa, Aya Fujishiro, Rie Nishimura, Masahiro Kawahara, Hitoshi Minamiguchi, Katsuyuki Kito, Akira Andoh.
  • Organizer: 第41回日本造血細胞移植学会総会
• [Presentation] 急性骨髄性白血病治療の新たな挑戦 (2018)
  • Author(s): 河原真大
  • Organizer: 近畿血液地方会
  • Invited
• [Presentation] Two cases with primary plasma cell leukemia. (2018)
  • Author(s): Yukako Teramoto, Masaki Iwasa, Ai Asai, Aya Fujishiro, Rie Nishimura, Masahiro Kawahara, Hitoshi Minamiguchi, Katsuyuki Kito, Akira Ando.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] sIL-2 receptor is one of the predictive marker of spontaneous regression in MTX-LPD. (2017)
  • Author(s): Saika M, Iwasa M, Nagai S, Asai A, Nishimura R, Furuya A, Kawahara M, Minamiguchi H, Kito K, Andoh A
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 当院における用量調整VRD療法 (2017)
  • Author(s): Asai A, Nagai S, Usui A, Kumode M, Iwasa M, Nishimura R, Kawahara M, Minamiguchi H, Kito K, Andoh A
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Aberrant repression of GFI1 super-enhancer by LSD1 plays an important role in leukemia programs in acute myeloid leukemia (2017)
  • Author(s): Goichi Tatsumi, Masahiro Kawahara, Akinori Kanai, Hirotaka Matsui, Ryusuke Yamamoto, Masakatsu Hishizawa, Toshiya Inaba, Takayoshi Suzuki, Akira Andoh, and Akifumi Takaori-Kondo
  • Organizer: 59th ASH Annual Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Ips Technology Revealed the Genetic and Functional Diversity Present in a Secondary AML Patient (2016)
  • Author(s): Kazuhisa Chonabayashi, Masahiro Kawahara, Akira Watanabe, Masahiro Nakamura, Masatoshi Nishizawa, Akifumi Takaori-Kondo, Shinya Yamanaka, and Yoshinori Yoshida,
  • Organizer: The 58th ASH annual meeting and exposition
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-03
• [Presentation] GFI1 enhancer silenced by LSD1 is important for myeloid differentiation blockage in AML (2016)
  • Author(s): Goichi Tatsumi, Masahiro Kawahara, Akinori Kanai, Hirotaka Matsui, Ryusuke Yamamoto, Masakatsu Hishizawa, Toshiya Inaba, Takayoshi Suzuki, Akira Andoh, and Akifumi Takaori-Kondo
  • Organizer: 第78回日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] A case report of multiple myeloma with central nervous system involvement (2016)
  • Author(s): 細羽 桜、岩佐 磨佐紀、南口 仁志、口分田美奈、臼井 亜沙子、永井 詩穂、大平 泰之、古屋 彩、瀬川 秀和、河原 真大、木藤 克之、安藤 朗
  • Organizer: 第78回日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Report of three cases of acute promyelocytic leukemia with CNS relapse (2016)
  • Author(s): 口分田美奈、臼井 亜沙子、大平 泰之、永井 詩穂、細羽 桜、古屋 彩、瀬川 秀和、河原 真大 南口 仁志、木藤 克之、安藤 朗
  • Organizer: 第78回日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] The silence of GFI1 enhancer by LSD1 is associated with myeloid differentiation block in AML (2016)
  • Author(s): Goichi Tatsumi, Masahiro Kawahara, Hirotaka Matsui, Masakatsu Hishizawa, Toshiya Inaba, Takayoshi Suzuki, Akira Andoh, and Akifumi Takaori-Kondo
  • Organizer: 第75回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06