Study for the mechanism of onset for myelodysplastic syndromes among atomic bomb survivors through temporal axis

• Project/Area Number: 20H03712
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nagasaki University
• Principal Investigator: Miyazaki Yasushi 長崎大学, 原爆後障害医療研究所, 教授 (40304943)
• Co-Investigator(Kenkyū-buntansha): 吉浦 孝一郎 長崎大学, 原爆後障害医療研究所, 教授 (00304931)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2022: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2021: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2020: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 骨髄異形成症候群 / 放射線 / ゲノム変異 / 原爆被爆者 / 放射線誘発造血器腫瘍 / ゲノム / 原爆放射線

Outline of Research at the Start

（１）被爆者MDS症例で発症以前から十年以上の時間軸に沿った末梢血検体のゲノム解析（２）1分子シーケンサーによる被爆者MDSのゲノム構造解析（３）造血器疾患未発症の近距離被爆者のクローン性造血の検討（４）マウスモデルを用いた被爆者MDSで高頻度に見られるATM遺伝子異常とMDS発症との関連の検討を実施し、放射線誘発造血器腫瘍の基本的な発症機構解明を目指す。

Outline of Final Research Achievements

Among Atomic Bomb survivors, the risk of myelodysplastic syndromes (MDS) is known to be elevated. We examined whether the genome alterations in radiation-induced MDS be different from those of de novo MDS or therapy-related MDS, and tried to reveal how radiation-induced MDS occurs. We had some data suggesting that the process of MDS development is different among radiation-induced, de novo or therapy-related MDS, and MDS among survivors seemed to obtain characteristic genome alterations.

Academic Significance and Societal Importance of the Research Achievements

造血器腫瘍の一つである骨髄異形成症候群（MDS）は、加齢を主たる要因とする自然発症例、抗がん剤治療による治療関連の場合、原爆放射線によって誘発される場合によって異なるゲノム変異を持つことが示された。これは、様々なタイプのゲノム変異を背景としてMDSという疾患が成り立っていることを示唆する。こうした病因によるゲノム変異の差異が他の造血器腫瘍、あるいは固形腫瘍においても見られる可能性があり、更に同一疾患であってもゲノム変異が異なっていれば、それぞれに適した個別治療開発の必要性を示している。

Research Products

• [Journal Article] Germ line <i>DDX41</i> mutations define a unique subtype of myeloid neoplasms (2023)
  • Author(s): Makishima H, Saiki R, Nannya Y, (17人省略), Kon A, (28人省略), Maciejewski JP, Ogawa S.
  • Journal Title: Blood Volume: 141 Issue: 5 Pages: 534-549
  • DOI: 10.1182/blood.2022018221
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Radiation-induced hematopoietic disorders (2022)
  • Author(s): 安東恒史 宮﨑泰司
  • Journal Title: Rinsho Ketsueki Volume: 63 Issue: 9 Pages: 981-990
  • DOI: 10.11406/rinketsu.63.981
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Amplified <i>EPOR</i>/<i>JAK2</i> Genes Define a Unique Subtype of Acute Erythroid Leukemia (2022)
  • Author(s): Takeda J, Kenichi Y, (9人省略), Kon A (12/41番目), (途中省略), Makishima H, Ogawa S
  • Journal Title: Blood Cancer Discovery Volume: 3 Issue: 5 Pages: 410-427
  • DOI: 10.1158/2643-3230.bcd-21-0192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN (2022)
  • Author(s): Dohner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Miyazaki Y, et al.
  • Journal Title: Blood Volume: 140 Issue: 12 Pages: 1345-1377
  • DOI: 10.1182/blood.2022016867
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Volasertib as a monotherapy or in combination with azacitidine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia: summary of three phase I studies. (2022)
  • Author(s): Platzbecker U, Chromik J, Handa H, Strickland S, Miyazaki Y, Wermke M, Sakamoto W, Tachibana Y, Taube T, Germing U.
  • Journal Title: BMC Cancer Volume: 22 Issue: 1 Pages: 569-569
  • DOI: 10.1186/s12885-022-09622-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prospective comparison of outcomes with azacitidine and decitabine in patients with AML ineligible for intensive chemotherapy (2022)
  • Author(s): Zeidan AM, Fenaux P, Gobbi M, Mayer J, Roboz GJ, Krauter J, Robak T, Kantarjian HM, Jedrzejczak WW, Thomas X, Ojeda-Uribe M, Miyazaki Y, Min YH, et al.
  • Journal Title: Blood Volume: 140 Issue: 3 Pages: 285-289
  • DOI: 10.1182/blood.2022015832
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Outcome of therapy‐related myelodysplastic syndrome and oligoblastic acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: A propensity score matched analysis (2022)
  • Author(s): Itonaga Hidehiro、Kida Michiko、Hamamura Atsushi、Uchida Naoyuki、Ozawa Yukiyasu、Fukuda Takahiro、Ueda Yasunori、Kataoka Keisuke、Katayama Yuta、Ota Shuichi、Matsuoka Ken‐ichi、Kondo Tadakazu、Eto Tetsuya、Kanda Junya、Ichinohe Tatsuo、Atsuta Yoshiko、Miyazaki Yasushi、Ishiyama Ken
  • Journal Title: Hematological Oncology Volume: 40 Issue: 4 Pages: 752-762
  • DOI: 10.1002/hon.2991
  • Peer Reviewed
• [Journal Article] No clear survival benefit of azacitidine for lower‐risk myelodysplastic syndromes: A retrospective study of Nagasaki (2020)
  • Author(s): Toriyama Eo、Hata Tomoko、Yokota Ken‐ichi、Chiwata Masahiko、Kamijo Rena、Hashimoto Miki、Taguchi Masataka、Horai Makiko、Matsuo Masatoshi、Matsuo Emi、Takasaki Yumi、Kawaguchi Yasuhisa、Itonaga Hidehiro、Sato Shinya、Ando Koji、Sawayama Yasushi、Taguchi Jun、Imaizumi Yoshitaka、Miyazaki Yasushi
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4490-4499
  • DOI: 10.1111/cas.14653
  • Peer Reviewed / Open Access
• [Journal Article] Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes (2020)
  • Author(s): Bernard E, Nannya Y, Hasserjian RP, Ogawa S, Papaemmanuil E
  • Journal Title: Nat Med Volume: 26(10) Issue: 10 Pages: 1549-1556
  • DOI: 10.1038/s41591-020-1008-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Molecular Landscape of Myeloid Neoplasms with Der(1;7)(q10;p10) (2022)
  • Author(s): Okuda R, Ochi Y, Hellstrom-Lindberg E, Torsten Haferlach, Chiba S, Sezaki S, Shih L-Y, Miyazaki Y, Yoshida Y, Ogawa S, et al.
  • Organizer: 第64回アメリカ血液学会
  • Int'l Joint Research
• [Presentation] Dynamics of Mortality and Transformation Risk within Different Risk Groups of Patients with Myelodysplastic Syndromes Stratified According to the IPSS-R - Comparison of Treated and Untreated Patients and Consequences for the Description of Risk Categories. (2022)
  • Author(s): Pfeilstocker M, Tuechler H, Ades L, Cermak J, Chermat F, Della Porta MG, Fenaux P, Garcia-Manero G, Miyazaki Y, et al.
  • Organizer: 第64回アメリカ血液学会
  • Int'l Joint Research
• [Presentation] Germline Risks and Clinical Impacts of DDX41 Mutations in Myeloid Malignancies (2022)
  • Author(s): Makishima H, Saiki R, Nannya Y, Korotev SC, Gurnari C, Takeda J, Momozawa Y, Best S, Krishnamurthy P, Miyazaki Y, Ogawa S, et al.
  • Organizer: 第64回アメリカ血液学会
  • Int'l Joint Research
• [Presentation] Placebo-Controlled Phase II Study of TIM-3 Inhibition with Sabatolimab Added to Hypomethylating Agents (HMAs) in Adult Patients with Higher-Risk Myelodysplastic Syndromes (MDS) (2022)
  • Author(s): Zeidan A, Ando K, Rauzy O, Turgut M, Wang MC, Cairoli R, Hou HA, Kwong YL, Sangerman MA, Miyazaki Y, Platzbecker U, et al.
  • Organizer: 第64回アメリカ血液学会
  • Int'l Joint Research
• [Presentation] Post-azacitidine clone size predicts long-term clinical outcome of patients with MDS and AML. (2021)
  • Author(s): Nannya Y, Miyazaki Y, Ogawa S, et al.
  • Organizer: 第83回日本血液学会学術集会
  • Int'l Joint Research
• [Presentation] Myeloid neoplasms with germline and somatic DDX41 mutations. (2021)
  • Author(s): Makishima H, Miyazaki Y, Ogawa S, et al.
  • Organizer: 第83回日本血液学会学術集会
  • Int'l Joint Research
• [Presentation] Differences in clinical features between MDS among atomic bomb survivors and therapy-related MDS. (2021)
  • Author(s): Horai M, Toriyama E, Miyazaki Y, et al.
  • Organizer: 第83回日本血液学会学術集会
  • Int'l Joint Research
• [Presentation] Molecular International Prognosis Scoring System for Myelodysplastic Syndromes. (2021)
  • Author(s): Bernard E, Greenberg P, Miyazaki Y, Papaemmanuil E, et al.
  • Organizer: 63rd American Sosiety of Hematology Annual Meting and Exposition
  • Int'l Joint Research
• [Presentation] Comparison of cytogenetic aberration between MDS in A-bomb survivors and therapy-related MDS (2020)
  • Author(s): Makiko Horai，Shinya Sato，Eo Toriyama, Miki Hashimoto, Masatoshi Matsuo，Masako Iwanaga, Tatsuro Jo，Yumi Takasaki， Hideki Tsushima，Shinichiro Yoshida， Koji Ando， Yasushi Sawayama，Yoshitaka Imaizumi，Tomoko Hata，Yukiyoshi Moriuchi，Yasushi Miyazaki
  • Organizer: 第82回 日本血液学会学術集会
  • Int'l Joint Research