Molecular pathogenesis of bone marrow failure elucidated by comprehensive sequencing.

2016 Fiscal Year Annual Research Report

• Project/Area Number: 16H05338
• Research Institution: Kyoto University
• Principal Investigator: 牧島 秀樹 京都大学, 医学研究科, 講師 (40402127)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 骨髄不全症候群 / 骨髄異形成症候群 / 二次性白血病 / タイプ1変異 / タイプ2変異 / 再生不良性貧血 / 発作性夜間血色素尿症

Outline of Annual Research Achievements

本研究の目的は、骨髄不全症候群におけるゲノムおよびトランスクリプトームの異常を解析することにより、骨髄不全・クローン選択・白血病化に深く関わる病因・病態を明らかにすることである。平成28年度には、当初の予定通り、①全ゲノムシーケンス、②全トランスクリプトームシーケンス、③クローン構造の解析、④マウスモデルを用いた機能解析を行った。このうち、特記すべきは、クローン構造の解析による成果である。骨髄不全症候群のうち、最も白血病化を起こしやすい骨髄異形成症候群（200例）において、ゲノム上の全遺伝子について網羅的な変異解析をすることにより、クローン選択に関する新たな知見を明らかにした（Makishima et al. Nat Genet 2017）。つづいて、世界最大コホートである2000例以上のドライバー遺伝子のシーケンス解析をすることにより、高リスク骨髄異形成症候群症例から二次性白血病に進展する際に高頻度に獲得されるタイプ1異常（FLT3、PTPN11、WT1、IDH1、NPM1、IDH2、NRAS変異）と、低リスクから高リスクに骨髄異形成症候群が進行する際に獲得されるタイプ2異常（TP53、GATA2、KRAS、RUNX1、STAG2、ASXL1、ZRSR2、TET2変異）を明らかにした。また、白血病化を起こしにくい遺伝子異常（SF3B1変異）をも明らかにした。以上の結果は、時系列で複数回サンプリングした検体を用いて検証が行われ、タイプ1変異は明らかに、臨床経過中にクローンサイズが増加することが確認された。これらの成果は、プレスリリースなどにより広く一般に公開され、情報が共有されている。抽出された遺伝子は、病期進展を予測するバイオマーカーとして使用され、クリニカルシーケンスに採用される可能性もあり前向き試験による検証が待たれる。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

予定していた全ゲノムシーケンス、全トランスクリプトームシーケンス、クローン構造の解析、マウスモデルを用いた機能解析は順調に行われ、これらのうち、クローン構造の解析においては、予想以上の成果が上がっている。

Strategy for Future Research Activity

骨髄不全症候群のうち、最も白血病へ進展する頻度の高い骨髄異形成症候群における解析を優先しておこない、並行して、再生不良性貧血および発作性夜間血色素尿症に関する解析も行う。全ゲノムおよびトランスクリプトームシーケンスに関しても引き続き症例数を蓄積し、これまでのシーケンス解析結果と関連させて、新たな病因の解明につなげる。特に、再生不良性貧血に関しては、すでに論文を準備中である。さらに、マウスモデルを用いた機能解析に関しても、SRSF2変異マウスに関して詳細な解析を行って、成果を発表する準備段階にある。

Research Products

• [Int'l Joint Research] Cleveland Clinic/NIH/Albert Einstein College of Medicine(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Cleveland Clinic/NIH/Albert Einstein College of Medicine
  • # of Other Institutions: 3
• [Int'l Joint Research] MLL/University Hospital Essen(Germany)
  • Country Name: Germany
  • Counterpart Institution: MLL/University Hospital Essen
• [Int'l Joint Research] Pavia University(Italy)
  • Country Name: Italy
  • Counterpart Institution: Pavia University
• [Int'l Joint Research] Radboud University/University of Amsterdam(Netherlands)
  • Country Name: Netherlands
  • Counterpart Institution: Radboud University/University of Amsterdam
• [Int'l Joint Research] Chang Gung University(台湾)
  • Country Name: その他の国・地域
  • Counterpart Institution: Chang Gung University
• [Int'l Joint Research]
  • # of Other Countries: 2
• [Journal Article] Dynamics of clonal evolution in myelodysplastic syndromes. (2017)
  • Author(s): Makishima H, Yoshizato T, Yoshida K et al., Ogawa S, Maciejewski JP.
  • Journal Title: Nat Genet. Volume: 49 Pages: 204-212
  • DOI: 10.1038/ng.3742.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular features of early onset adult myelodysplastic syndrome. (2017)
  • Author(s): Hirsch CM, Przychodzen BP, Radivoyevitch T, Patel B, Thota S, Clemente MJ, Nagata Y, LaFramboise T, Carraway H, Nazha A, Sekeres MA, Makishima H, Maciejewski JP.
  • Journal Title: Haematologica. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.3324/haematol.2016.159772.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A myeloid tumor suppressor role for NOL3. (2017)
  • Author(s): Stanley RF, Piszczatowski RT, Bartholdy B, Mitchell K, McKimpson WM, Narayanagari S, Walter D, Todorova TI, Hirsch C, Makishima H, Will B, McMahon C, Gritsman K, Maciejewski JP, Kitsis RN, Steidl U.
  • Journal Title: J Exp Med. Volume: 214 Pages: 753-771
  • DOI: 10.1084/jem.20162089.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of genetic alterations in stem-cell transplantation for myelodysplasia and secondary acute myeloid leukemia. (2017)
  • Author(s): Yoshizato T et al., Makishima H, Ogawa S.
  • Journal Title: Blood. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1182/blood-2016-12-754796.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Deletion of Ptpn1 induces myeloproliferative neoplasm. (2017)
  • Author(s): Jobe F, Patel B, Kuzmanovic T, Makishima H, Yang Y, Przychodzen B, Hutchison RE, Bence KK, Maciejewski JP, Mohi G.
  • Journal Title: Leukemia. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1038/leu.2017.31.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Recurrent genetic defects on chromosome 5q in myeloid neoplasms. (2017)
  • Author(s): Hosono N, Makishima H, Mahfouz R, Przychodzen B, Yoshida K, Jerez A, LaFramboise T, Polprasert C, Clemente MJ, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Sanada M, Cui E, Verma AK, McDevitt MA, List AF, Saunthararajah Y, Sekeres MA, Boultwood J, Ogawa S, Maciejewski JP.
  • Journal Title: Oncotarget. Volume: 8 Pages: 6483-6495
  • DOI: 10.18632/oncotarget.14130.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene mutations in myelodysplastic syndromes. (2016)
  • Author(s): Makishima H, Ogawa S.
  • Journal Title: Rinsho Ketsueki. Volume: 57 Pages: 2543-2553
  • DOI: 10.11406/rinketsu.57.2543.
  • Peer Reviewed
• [Journal Article] Gene mutations in bone marrow failure syndromes. (2016)
  • Author(s): Yoshizato T, Makishima H.
  • Journal Title: Rinsho Ketsueki. Volume: 57 Pages: 2519-2525
  • DOI: doi: 10.11406/rinketsu.57.2519.
  • Peer Reviewed
• [Journal Article] Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms. (2016)
  • Author(s): Mori T, Nagata Y, Makishima H, et al.
  • Journal Title: Leukemia. Volume: 30 Pages: 2270-2273
  • DOI: 10.1038/leu.2016.212.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Somatic mosaicism in chronic myeloid leukemia in remission. (2016)
  • Author(s): Mitani K, Nagata Y, Sasaki K, Yoshida K, Chiba K, Tanaka H, Shiraishi Y, Miyano S, Makishima H, Nakamura Y, Nakamura Y, Ichikawa M, Ogawa S.
  • Journal Title: Blood. Volume: 128 Pages: 2863-2866
  • Peer Reviewed
• [Journal Article] Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. (2016)
  • Author(s): Negoro E, Radivoyevitch T, Polprasert C, Adema V, Hosono N, Makishima H, Przychodzen B, Hirsch C, Clemente MJ, Nazha A, Santini V, McGraw KL, List AF, Sole F, Sekeres MA, Maciejewski JP.
  • Journal Title: Leukemia. Volume: 30 Pages: 2405-2409
  • DOI: 10.1038/leu.2016.228.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic therapy as a novel approach for GFI136N-associated murine/human AML. (2016)
  • Author(s): Botezatu L, Michel LC, Helness A, Vadnais C, Makishima H, Hones JM, Robert F, Vassen L, Thivakaran A, Al-Matary Y, Lams RF, Schutte J, Giebel B, Gorgens A, Heuser M, Medyouf H, Maciejewski J, Duhrsen U, Moroy T, Khandanpour C.
  • Journal Title: Exp Hematol. Volume: 44 Pages: 713-726
  • DOI: 10.1016/j.exphem.2016.05.004.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GFI1(36N) as a therapeutic and prognostic marker for myelodysplastic syndrome. (2016)
  • Author(s): Botezatu L, Michel LC, Makishima H et al.
  • Journal Title: Exp Hematol. Volume: 44 Pages: 590-595
  • DOI: 10.1016/j.exphem.2016.04.001.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GFI1 as a novel prognostic and therapeutic factor for AML/MDS. (2016)
  • Author(s): Hones JM et al.,Hergenhan SM, Thivakaran A, Schutte J, Al-Matary YS, Lams RF, Fraszscak J, Makishima H et al.
  • Journal Title: Leukemia. Volume: 30 Pages: 1237-1245
  • DOI: 10.1038/leu.2016.11.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of allogeneic hematopoietic cell transplant in patients with myeloid neoplasms carrying spliceosomal mutations. (2016)
  • Author(s): Hamilton BK, Visconte V, Jia X, Tabarroki A, Makishima H, Hasrouni E, Abounader D, Kalaycio M, Sekeres MA, Sobecks R, Duong Liu H, Bolwell B, Maciejewski JP, Copelan E, Tiu RV.
  • Journal Title: Am J Hematol. Volume: 91 Pages: 406-409
  • DOI: 10.1002/ajh.24306.
  • Peer Reviewed / Int'l Joint Research
• [Presentation] The Impact of Clonal Dynamics on Prognosis and Outcome in Myelodysplastic Syndromes. (2016)
  • Author(s): Hideki Makishima et al.
  • Organizer: 58th Annual Meeting of American Society of Hematology.
  • Place of Presentation: San Diego, USA.
  • Year and Date: 2016-12-05 – 2016-12-05
• [Presentation] Distinct genetic events in PNH and AA. (2016)
  • Author(s): Hideki Makishima.
  • Organizer: 2016 Annual Scientific Meeting, The International PNH Interest Group.
  • Place of Presentation: San Diego, USA.
  • Year and Date: 2016-12-02 – 2016-12-02
  • Int'l Joint Research / Invited
• [Presentation] Clinical impact of somatic mutations on clonal evolution in myelodysplastic syndromes. (2016)
  • Author(s): Hideki Makishima et al.
  • Organizer: The 75th Annual Meeting of the Japanese Cancer Association.
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-30 – 2016-10-30
• [Presentation] Mutational panel for following clonal evolution in myelodysplastic syndromes. (2016)
  • Author(s): Hideki Makishima et al.
  • Organizer: The 78th Annual Meeting of the Japanese Society of Hematology.
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13 – 2016-10-13
• [Presentation] Clonal dynamics in myelodysplastic syndromes. (2016)
  • Author(s): Hideki Makishima.
  • Organizer: The Japanese Society of Medical Oncology Annual Meeting.
  • Place of Presentation: 神戸
  • Year and Date: 2016-07-29 – 2016-07-29
• [Presentation] DYNAMICS OF CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES. (2016)
  • Author(s): Hideki Makishima et al.
  • Organizer: 21st Congress of European Hematology Association.
  • Place of Presentation: Copenhagen, Denmark.
  • Year and Date: 2016-06-11 – 2016-06-11
• [Presentation] MDS genomics and its clinical implication. (2016)
  • Author(s): Hideki Makishima.
  • Organizer: The Fifth National Conference on Hematological Oncology.
  • Place of Presentation: Nanjing, China.
  • Year and Date: 2016-05-21 – 2016-05-21
  • Int'l Joint Research / Invited
• [Presentation] Clonal dynamics in myelodysplastic syndromes. (2016)
  • Author(s): Hideki Makishima.
  • Organizer: 5th International Conference on Myelodysplastic Syndromes, European School of Hematology.
  • Place of Presentation: Estoril, Portugal.
  • Year and Date: 2016-04-14 – 2016-04-14
  • Int'l Joint Research / Invited
• [Remarks] ライフサイエンスレビュー
  • URL: http://first.lifesciencedb.jp/archives/15045
• [Remarks] 京都大学 プレスリリース
  • URL: http://www.kyoto-u.ac.jp/ja/research/research_results/2016/161220_1.html
• [Remarks] 東京大学 医科学研究所 発表論文解説
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/research/papers/_2.php