Understanding the molecular mechanisms through histone acetyl-transferase in the differentiation therapy

• Project/Area Number: 18K16099
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Juntendo University
• Principal Investigator: Shirane Shuichi 順天堂大学, 医学部, 助教 (40760129)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 急性前骨髄性白血病 / ATRA / ヒストンアセチル基転移酵素 / 分化誘導療法 / 急性前骨髄球性白血病 / レチノイン酸誘導体

Outline of Final Research Achievements

This study aimed to comprehensively elucidate the transcriptional network regulated by a differentiation-inducing reagent and to clarify the involvement of histone acetyltransferases in the differentiation, which will contribute to the establishment of basis for the development of differentiation-inducing therapies that can be applied to the treatment of a wider range of cancers. This study revealed a group of genes involved in the process of differentiation of acute promyelocytic leukemia cells into neutrophils by all-transretinoic acid (ATRA), which is used clinically as differentiation-inducing drugs for hematological malignancies. Furthermore, the role of histone acetyltransferases, which are involved in the regulation of the expression of a wide range of genes among these genes, in ATRA-induced neutrophil differentiation was clarified.

Academic Significance and Societal Importance of the Research Achievements

本研究により明らかになった分化誘導性遺伝子の候補を検索することで、今後、広範な腫瘍に効果的な分化誘導薬の開発が期待される。これにより、副作用の強い化学療法剤に代わる分化誘導薬が、急性前骨髄球性白血病以外の腫瘍においても開発されれば、抗がん剤の選択肢が増えるだけでなく、がん患者のQOL向上に結びつくことなどから、本研究の成果は学術的にも社会的にも極めて意義深いと言える。

Research Products

• [Journal Article] Allogeneic Hematopoietic Stem Cell Transplantation for Post-essential Thrombocythemia and Post-polycythemia Vera Myelofibrosis (2020)
  • Author(s): Murata M, Suzuki R, Nishida T, Shirane S, Shimazu Y, Minami Y, Mori T, Doki N, Kanda Y, Uchida N, Tanaka M, Ishikawa J, Togitani K, Fukuda T, Ichinohe T, Atsuta Y, Nagamura-Inoue T, Kiyoi H.
  • Journal Title: Internal Medicine Volume: 59 Issue: 16 Pages: 1947-1956
  • DOI: 10.2169/internalmedicine.4375-19
  • NAID: 130007887720
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-08-15
  • Peer Reviewed / Open Access
• [Journal Article] Bone turnover markers as an aid to monitor osteoporosis following allogeneic hematopoietic stem cell transplantation (2020)
  • Author(s): Kurosawa Shuhei, Doki Noriko, Senoo Yasushi, Kishida Yuya, Nagata Akihito, Yamada Yuta, Konishi Tatsuya, Kaito Satoshi, Yoshifuji Kota, Matsuyama Naoki, Shirane Shuichi, et al
  • Journal Title: Annals of Hematology Volume: 99 Issue: 8 Pages: 1873-1882
  • DOI: 10.1007/s00277-020-04090-7
  • Peer Reviewed
• [Presentation] The development of IVLBCL after the treatment for PNCSL (2020)
  • Author(s): Yoko Edahiro, Tomoiku Takaku, Yasutaka Fukuda, Sakiko Harada, Shintaro Kinoshita, Tadaaki Inano, Shuichi Shirane, Yasuharu Hamano, Norio Komatsu
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Two cases of R-CHOP therapy combined with eltrombopag for treatment DLBCL complicated with AA (2020)
  • Author(s): Yasutaka Fukuda, Tomoiku Takaku, Chiho Furuya, Shuichi Shirane, Yoko Edahiro, Yasuharu Hamano, Norio Komatsu
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 全トランス型レチノイン酸による白血病細胞分化制御因子の同定 (2019)
  • Author(s): 角南義孝、荒木真理人、山本誠司、白根脩一、堀内祥行、辻岡一也、茂櫛薫、山口茂夫、今井美沙、森下総司、大坂顯通、小松則夫
  • Organizer: 第29回日本サイトメトリー学会学術集会