低線量被曝からMDS発症に至る疫学的解析および分子発症プロセスの解明

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25461422
• Research Institution: Bunkyo Gakuin University
• Principal Investigator: 原田 結花 文京学院大学, 保健医療学部, 教授 (50379848)
• Co-Investigator(Kenkyū-buntansha): 原田 浩徳 順天堂大学, 医学部, 准教授 (10314775)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 低線量被曝 / 骨髄異形成症候群 / RUNX1変異 / 放射線傷害耐性

Outline of Annual Research Achievements

骨髄異形成症候群（MDS）の発症機構の主要部を担う遺伝子異常の一つであるRUNX1変異は，化学療法や放射線療法後の治療関連造血器腫瘍症例に高率に認められ，放射線や化学療法によるMDSのバイオマーカーの１つと考えられる。原爆被爆者では遠距離直爆例などの低線量被曝症例にも認められることから，これまでほとんど解析されていなかった低線量被曝に注目し，低線量被曝後非常に長い期間を経てMDSを発症した症例のRUNX1変異を中心とした遺伝子異常の解明を試みた。
低線量被曝が疑われる新規または保存患者サンプルを用いてRUNX1変異などの遺伝子異常を検索した結果，2km以内の直接被爆者よりもむしろやや多い割合で変異が認められた。さらに，低線量被曝MDS患者に認められたRUNX1変異が，様々な遺伝子異常と協調して造血機能破綻をきたすことを解明し，被曝後年月を経てMDSを発症する機序が少しずつ明らかになりつつある。
最近，RUNX1欠損マウスの造血幹細胞は放射線に対する感受性が低いことが明らかにされた。すなわち，RUNX1欠損造血幹細胞は，放射線傷害によるアポトーシスから逸脱し，いわば耐性を獲得していると推測される。このことは，放射線によりRUNX1変異が生じやすいという仮説に加え，既存のRUNX1変異を有する造血幹細胞が放射線傷害に耐性で残存し，そこからクローン性に増殖することも想定される。後者の仮説を検証するために，MDS未発症の低線量被曝者におけるRUNX1変異を評価するRUNX1変異微小クローンの検出法開発を行った。

Research Products

• [Journal Article] Genetic basis of myeloid transformation in familial platelet disorder/acute myeloid leukemia patients with haploinsufficient RUNX1 allele (2016)
  • Author(s): Sakurai M, Kasahara H, Yoshida K, Yoshimi A, Kunimoto H, Watanabe N, Shiraishi Y, Chiba K, Tanaka H, Harada Y, Harada H, Kawakita T, Kurokawa M, Miyano S, Takahashi S, Ogawa S, Okamoto S, Nakajima H
  • Journal Title: Blood Cancer J Volume: 6 Pages: e392
  • DOI: 10.1038/bcj.2015.81
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan (2016)
  • Author(s): Yoshimi A, Toya T, Nannya Y, Takaoka K, Kirito K, Ito E, Nakajima H, Hayashi Y, Takahashi T, Moriya-Saito A, Suzuki K, Harada H, Komatsu N, Usuki K, Ichikawa M, Kurokawa M
  • Journal Title: Ann Oncol Volume: 27(5) Pages: 887-895
  • DOI: 10.1093/annonc/mdw066
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 慢性骨髄単球性白血病（CMML：病態解明の進歩と治療の現在） (2016)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 臨床血液 Volume: 57(2) Pages: 147-155
  • DOI: 10.11406/rinketsu.57.147
  • Peer Reviewed
• [Journal Article] Recent advances in myelodysplastic syndromes: molecular pathogenesis and its implications for targeted therapies (2015)
  • Author(s): Harada H, Harada Y
  • Journal Title: Cancer Sci Volume: 106(4) Pages: 329-336
  • DOI: 10.1111/cas.12614
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A C-terminal mutant of C/EBPalpha (C/EBPalpha-C) down-regulates Csf1r, a potent accelerator in the progression of AML with C/EBPalpha-C (2015)
  • Author(s): Togami K, Kitaura J, Uchida T, Inoue D, Nishimura K, Kawabata KC, Nagase R, Horikawa S, Izawa K, Fukuyama T, Nakahara F, Oki T, Harada Y, Harada H, Aburatani H, Kitamura T
  • Journal Title: Exp Hematol Volume: 43(4) Pages: 300-308
  • DOI: 10.1016/j.exphem.2014.11.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS (2015)
  • Author(s): Inoue D, Kitaura J, Matsui H, Hou H-A, Chou W-C, Nagamachi A, Kawabata K, Togami K, Nagase R, Horikawa S, Saika M, Micol J-B, Hayashi Y, Harada Y, Harada H, Inaba T, Tien H-F, Abdel-Wahab O, Kitamura T
  • Journal Title: Leukemia Volume: 29(4) Pages: 847-857
  • DOI: 10.1038/leu.2014.301
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Long noncoding RNA, CCDC26, controls myeloid leukemia cell growth through regulation of KIT expression (2015)
  • Author(s): Hirano T, Yoshikawa R, Harada H, Harada Y, Ishida A, Yamazaki T
  • Journal Title: Mol Cancer Volume: 14(1) Pages: 90
  • DOI: 10.1186/s12943-015-0364-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A randomized controlled trial comparing darbepoetin alfa doses in red blood cell transfusion-dependent patients with low- or intermediate-1 risk myelodysplastic syndromes (2015)
  • Author(s): Jang JH, Harada H, Shibayama H, Shimazaki R, Kim HJ, Sawada K, Mitani K
  • Journal Title: Int J Hematol Volume: 102(4) Pages: 401-412
  • DOI: 10.1007/s12185-015-1862-5
  • Peer Reviewed
• [Journal Article] 白血病の発症機序と分子標的治療 (2015)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 臨床雑誌「内科」 Volume: 116(2) Pages: 191-197
• [Journal Article] 【骨髄異形成症候群（MDS）－最近の進歩－】 基礎：MDSの分子病態 (2015)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 最新医学 Volume: 70(11) Pages: 2069-2075
• [Journal Article] 【特集：血液内科診療の展望】 骨髄異形成症候群診療の展望 (2015)
  • Author(s): 原田浩徳
  • Journal Title: 日医大医会誌 Volume: 11(4) Pages: 187-191
• [Journal Article] 【特集：急性骨髄性白血病のゲノム解析～現状と展望～】 Germline変異と急性骨髄性白血病 (2015)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液フロンティア Volume: 25(11) Pages: 1607-1615
• [Journal Article] 【特集／骨髄異形成症候群（MDS）の病態解析と治療の進歩】 メチル化阻害薬の効果予測とゲノム解析 (2015)
  • Author(s): 原田結花，原田浩徳
  • Journal Title: 血液内科 Volume: 71(5) Pages: 593-599
• [Presentation] Dysregulation of RUNX1 Plays a Critical Role in the Progression of Myelodysplastic Syndromes (2016)
  • Author(s): 原田浩徳
  • Organizer: 第20回造血器腫瘍研究会
  • Place of Presentation: かずさアーク（千葉県木更津市）
  • Year and Date: 2016-02-12 – 2016-02-13
• [Presentation] HIF-1a Pathway, As a Signal Funnel for Genetic, Epigenetic, and Metabolic Aberrations, Is Sufficient and Essential for MDS Development (2015)
  • Author(s): Hayashi Y, Zhang Y, Yan X, Choi K, Sashida G, Dong Y , Xu Z, Wu L, Chen A, Sun X, Olsson A, Harada H, Shih L-Y, Tse W, Bridges J, Witte DP, Wang Q , Caligiuri MA, Grimes HL, Nimer SD, Xiao Z, Huang G
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco, CA (USA)
  • Year and Date: 2015-12-06 – 2015-12-09
  • Int'l Joint Research
• [Presentation] Dysregulation of RUNX1 Plays a Critical Role in the Progression of Myelodysplastic Syndromes (2015)
  • Author(s): Sakurai H, Harada Y, Matsui H, Nakajima H, Kitamura T, Komatsu N, Harada H
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco, CA (USA)
  • Year and Date: 2015-12-06 – 2015-12-09
  • Int'l Joint Research
• [Presentation] A Patient-Derived EZH2 Mutant Induces MDS-like Diseases with Derepressed ABCG2 Expression in Mice (2015)
  • Author(s): Kawabata KC, Inoue D, Kitaura J, Harada Y, Goyama S, Harada H, Aburatani H, Kitamura T
  • Organizer: 57th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco, CA (USA)
  • Year and Date: 2015-12-06 – 2015-12-09
  • Int'l Joint Research
• [Presentation] Overexpression of RUNX1 short isoform plays a pivotal role in the development of myelodysplastic syndromes (2015)
  • Author(s): Harada H, Sakurai H, Harada Y, Kitamura T, Komatsu N
  • Organizer: The RUNX Transcription Factors in Development and Disease
  • Place of Presentation: Rehovot (Israel)
  • Year and Date: 2015-10-18 – 2015-10-21
  • Int'l Joint Research / Invited
• [Presentation] Nationwide epidemiological survey of familial platelet disorder in Japan (2015)
  • Author(s): Toya T, Yoshimi A, Takaoka K, Nannya Y, Kirito K, Ito E, Nakajima H, Hayashi Y, Takahashi T, Moriya-Saito A, SuzukiK, Harada H, Komatsu N, Usuki K, Ichikawa M, Kurokawa M
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: ホテル日航金沢 他（石川県金沢市）
  • Year and Date: 2015-10-16 – 2015-10-18
• [Presentation] Overexpression of RUNX1 short isoform plays a pivotal role in the development of MDS/MPN (2015)
  • Author(s): Sakurai H, Harada Y, Matsui H, Nakajima H, Doki N, Kakihana K, Ohashi K, Kitamura T, Komatsu N, Harada H
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: ホテル日航金沢 他（石川県金沢市）
  • Year and Date: 2015-10-16 – 2015-10-18
• [Presentation] Truncated form EZH2 promotes stemness of MDS via derepression of stemness related genes (2015)
  • Author(s): Kawabata KC, Inoue D, Hayashi Y, Harada H, Goyama S, Kitaura J, Kitamura T
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: ホテル日航金沢 他（石川県金沢市）
  • Year and Date: 2015-10-16 – 2015-10-18
• [Presentation] Analysis of MDS mice model induced by ASXL1 and RUNX1 mutations. (2015)
  • Author(s): Nagase R, Inoue D, Saika M, Hou H-A, Chou W-C, Kawabata KC, Harada H, Goyama S, Hwai-Fang T, Kitamura T
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: ホテル日航金沢 他（石川県金沢市）
  • Year and Date: 2015-10-16 – 2015-10-18
• [Presentation] Investigation of a causal gene of familial myelodysplastic syndromes (2015)
  • Author(s): Takaoka K, Kawazu M, Yoshimi A, Toya T, Kobayashi T, Nannya Y, Ueno H, Suzuk K, Harada H, Manabe A, Hayashi Y, Mano H, Kurokawa M
  • Organizer: The 77th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: ホテル日航金沢 他（石川県金沢市）
  • Year and Date: 2015-10-16 – 2015-10-18
• [Presentation] Overexpression of RUNX1 short isoform plays a pivotal role in the development of MDS/MPN (2015)
  • Author(s): Sakurai H, Harada Y, Matsui H, Nakajima H, Doki N, Kakihana K, Ohashi K, Kitamura T, Komatsu N, Harada H
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: （愛知県名古屋市）
  • Year and Date: 2015-10-08 – 2015-10-10
• [Presentation] Inactivation of EZH2 by truncated form mutation depresses stemness-related genes and promote myelodysplastic syndrome (2015)
  • Author(s): Kawabata KC, Inoue D, Hayashi Y, Harada H, Goyama S, Kitaura J, Kitamura T
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08 – 2015-10-10
• [Presentation] Nationwide epidemiological survey of familial platelet disorder in Japan (2015)
  • Author(s): Toya T, Yoshimi A, Nannya Y, Takaoka K, Kirito K, Nakajima H, Hayashi Y, Takahashi T, Harada H, Komatsu N, Ichikawa M, Kurokawa M
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08 – 2015-10-10
• [Presentation] A candidate causal gene of familial myelodysplastic syndromes (2015)
  • Author(s): Takaoka K, Kawazu M, Yoshimi A, Toya T, Kobayashi T, Nannya Y, Ueno H, Harada H, Hayashi Y, Mano H, Kurokawa M
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08 – 2015-10-10
• [Presentation] Overexpression of RUNX1 short isoform plays a pivotal role in the development of myelodysplastic syndromes/ myeloproliferative neoplasms (2015)
  • Author(s): Sakurai H, Harada Y, Matsui H, Nakajima H, Kitamura T, Komatsu N, Harada H
  • Organizer: ISEH 44th Annual Scientific Meeting
  • Place of Presentation: Kyoto International Conference Center (Kyoto, Japan)
  • Year and Date: 2015-09-17 – 2015-09-19
  • Int'l Joint Research
• [Book] 骨髄異形成症候群（MDS）の基礎と臨床 改訂版，朝長万左男編，(分担執筆，MDSの遺伝子異常スペクトラムと臨床的意義) (2015)
  • Author(s): 原田結花，原田浩徳
  • Total Pages: 323（194-203）
  • Publisher: 医薬ジャーナル社
• [Book] Principles and Practice 血液・造血器・リンパ系，千葉 滋編（分担執筆，遺伝子検査） (2015)
  • Author(s): 原田結花，原田浩徳
  • Total Pages: 385（106-111）
  • Publisher: 文光堂