次世代シーケンサーを用いた骨髄異形成症候群の新規標的遺伝子の探索

• Project/Area Number: 12J04216
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: 発がん
• Research Institution: The University of Tokyo
• Principal Investigator: 吉田 健一 東京大学, 医学部附属病院, 特別研究員(DC2)
• Project Period (FY): 2012 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 2013: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2012: ¥900,000 (Direct Cost: ¥900,000)
• Keywords: 骨髄異形成症候群 / 遺伝子変異 / 次世代シーケンサー / 全エクソンシーケンス / コヒーシン / RNAスプライシング

Research Abstract

これまでに次世代シーケンサーを用いた骨髄異形成症候群(MDS)の全エクソンシーケンスおよびSNP arrayによるコピー数解析について200例の解析を行った。その中で、コヒーシン複合体関係の遺伝子(STAG2、RAD21、SMC1A、SMC3)、SETBP1、BCOR/BCORL1、RIT1などの遺伝子の変異について同定した(Kon et al., Nat Genet. 2013, Makishima et al., Nat Genet. 2013, Damm et al., Blood 2013, Gomez-Segui et al., Leukemia 2013)。コヒーシン複合体を構成する遺伝子の変異および欠失はMDSでは8%に認められ、変異・欠失のある症例では排他的にみられていて、4つの遺伝子の変異は共通のメカニズムで腫瘍化に関わっていると考えられた。SETBP7変異は予後不良と相関し、二次性の白血病への移行に関係していると考えられた。はさらに以前に我々の研究室で同定したU2AF1, SRSF2, SF3B1, ZRSR2などRNAスプライシング因子も含めて、104遺伝子について標的を絞ったmultiplexed barcoded sequencillgを944症例のMDS検体について行った。その結果、90%近い症例で1個以上の遺伝子変異が同定され、多くの高リスクのMDSや予後不良と相関する遺伝子変異が同定された。さらに、このうち14個の遺伝子を従来から予後予測に用いられていた臨床データと組み合わせることにより、従来のIPSSに比べて正確な予後予測が可能であることを報告した(Haferlach et al., Leukemia 2014)。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

次世代シーケンサーを用いた全エクソンシーケンス、multiplexed barcoded sequencingについてはほぼ当初の計画通りに行うことができ、その成果では予想以上に多くの新規標的遺伝子が同定されてきており、期待された以上の成果が得られた。

Strategy for Future Research Activity

今後はこれまでの研究で骨髄異形成症候群で遺伝子変異が同定されたRNAスプライシング因子、コヒーシン関係の遺伝子やSETBP1などについてマウスモデルを用いてMDS発症のメカニズムを解析していく予定である。

Research Products

• [Journal Article] Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. (2014)
  • Author(s): Sakata-Yanagimoto M, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 2 Pages: 171-175
  • DOI: 10.1038/ng.2872
  • Peer Reviewed
• [Journal Article] Tracing the development of acute myeloid leukemia in CBL syndrome (2014)
  • Author(s): Becker H, Yoshida K
  • Journal Title: Blood Volume: 123 Issue: 12 Pages: 1883-1886
  • DOI: 10.1182/blood-2013-10-533844
  • Peer Reviewed
• [Journal Article] Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. (2014)
  • Author(s): Haferlach T, Yoshida K
  • Journal Title: Leukemia Volume: 28 Pages: 241-247
  • Peer Reviewed
• [Journal Article] Recurrent genetic defects on chromosome 7q in myeloid neoplasms. (2014)
  • Author(s): Hosono N, Yoshida K
  • Journal Title: Leukemia Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Haploinsufficiency of Sf3b1 leads to compromised stem cell function but not to myelodysplasia. (2014)
  • Author(s): Matsunawa M, Yoshida K
  • Journal Title: Leukemia Volume: (Epub ahead of print) Issue: 9 Pages: 1-7
  • DOI: 10.1038/leu.2014.73
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic DICER1 mutations in sporadic pleuropulmonary blastoma. (2014)
  • Author(s): Seki M, Yoshida K
  • Journal Title: Cancer Res Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Whole-exome sequence analysis of ataxia telangiectasia-like phenotype. (2014)
  • Author(s): Hasewgawa S, Yoshida K
  • Journal Title: J Neurol Sci. Volume: (Epub ahead of print) Issue: 1-2 Pages: 86-90
  • DOI: 10.1016/j.jns.2014.02.033
  • Peer Reviewed
• [Journal Article] The landscape of somatic mutations in Down syndrome-related myeloid disorders. (2013)
  • Author(s): Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 11 Pages: 1293-1200
  • DOI: 10.1038/ng.2759
  • Peer Reviewed
• [Journal Article] Somatic SETBP1 mutations in myeloid malignancies. (2013)
  • Author(s): Makishima H, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 8 Pages: 942-946
  • DOI: 10.1038/ng.2696
  • Peer Reviewed
• [Journal Article] Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. (2013)
  • Author(s): Kon A, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 10 Pages: 1232-1237
  • DOI: 10.1038/ng.2731
  • Peer Reviewed
• [Journal Article] Integrated molecular analysis of clear-cell renal cell carcinoma. (2013)
  • Author(s): Sato Y, Yoshida K
  • Journal Title: Nature Genet. Volume: 45 Issue: 8 Pages: 860-867
  • DOI: 10.1038/ng.2699
  • Peer Reviewed
• [Journal Article] Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. (2013)
  • Author(s): Sakaguchi H, Yoshida K
  • Journal Title: Nature Genet. Volume: 46 Issue: 8 Pages: 937-941
  • DOI: 10.1038/ng.2698
  • Peer Reviewed
• [Journal Article] Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients. (2013)
  • Author(s): Hira A, Yoshida K
  • Journal Title: Blood Volume: 122 Issue: 18 Pages: 3206-3209
  • DOI: 10.1182/blood-2013-06-507962
  • Peer Reviewed
• [Journal Article] BCOR and BCORL1 mutations in myelodysplastic synd romes and related disorders. (2013)
  • Author(s): Damm F, Chesnais V, Nagata Y, Yoshida K, Scourzic L, Okuno Y, Itzykson R, Sanada M, Shiraishi Y, Gelsi-Boyer V, Renneville A, Miyano S, Mori H, Shih LY, Park S, Dreyfus F, Guerci-Bresler A, Solary E, Rose C, Cheze S, Prebet T, Vey N, Legentil M, Duffourd Y, de Botton S, Preudhomme C, Birnbaum D, Bernard OA, Ogawa S, Fontenav M, Kosmider O.
  • Journal Title: Blood Volume: 122(18) Issue: 18 Pages: 3169-77
  • DOI: 10.1182/blood-2012-11-469619
  • Peer Reviewed
• [Journal Article] Novel recurrent mutations in the RAS-like GTP-binding gene RIT1 in myeloid malignancies. (2013)
  • Author(s): Gomez-Segui I, Yoshida K
  • Journal Title: Leukemia Volume: 27 Pages: 1943-1946
  • Peer Reviewed
• [Journal Article] Normal neutrophil myosin HA localization in an immunofluorescence analysis can rule out MYH9 disorders. (2013)
  • Author(s): Kitamura K, Yoshida K
  • Journal Title: J Thromb Haemost. Volume: 11 Issue: 11 Pages: 2071-2073
  • DOI: 10.1111/jth.12406
  • Peer Reviewed
• [Journal Article] 骨髄異形成症候群・急性骨髄性白血病における全エクソン・全ゲノム解析 (2013)
  • Author(s): 吉田健一、小川誠司
  • Journal Title: 日本小児血液・がん学会雑誌 Volume: 50 Pages: 350-354
  • Peer Reviewed
• [Journal Article] ACTN1 Mutations Cause Congenital Macrothrombocytopenia (2013)
  • Author(s): 國島伸治、吉田健一
  • Journal Title: Am J Hum Genet Volume: 92 Issue: 3 Pages: 431-438
  • DOI: 10.1016/j.ajhg.2013.01.015
  • Peer Reviewed
• [Journal Article] Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS) (2013)
  • Author(s): 大場理恵、吉田健一
  • Journal Title: Ann Hematol Volume: 92 Issue: 1 Pages: 1-9
  • DOI: 10.1007/s00277-012-1564-5
  • Peer Reviewed
• [Journal Article] An empirical Bayesian framework for somatic mutation detectionfrom cancer genome sequencing data (2013)
  • Author(s): 白石友一、吉田健一
  • Journal Title: Nucleic Acids Res Volume: ([Epub ahead of print])
  • Peer Reviewed
• [Journal Article] Clonal selection in xenografted TAM recapitulates the evolutionary process of myeloid leukemia in Down syndrome. (2013)
  • Author(s): 才田聡、吉田健一
  • Journal Title: Blood Volume: ([Epub ahead of print])
  • Peer Reviewed
• [Journal Article] Deep sequencing in cancer research (2012)
  • Author(s): 吉田健一
  • Journal Title: Jpn J Clin Oncol Volume: 43 Pages: 110-115
  • Peer Reviewed
• [Journal Article] Novel splicing-factor mutations in juvenile myelomonocytic leukemia (2012)
  • Author(s): 滝田順子、吉田健一
  • Journal Title: Leukemia Volume: 26 Issue: 8 Pages: 1879
  • DOI: 10.1038/leu.2012.45
  • Peer Reviewed
• [Journal Article] SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). (2012)
  • Author(s): Meggendorfer M, Yoshida K
  • Journal Title: Blood Volume: 120 Issue: 15 Pages: 3080-3088
  • DOI: 10.1182/blood-2012-01-404863
  • Peer Reviewed
• [Journal Article] 骨髄異形成症候群におけるIDH1/2遺伝子変異 (2012)
  • Author(s): 吉田健一
  • Journal Title: 臨床血液 Volume: 53 Pages: 391-395
  • NAID: 10030830863
  • Peer Reviewed
• [Journal Article] 骨髄異形成症候群の新たな分子メカニズム (2012)
  • Author(s): 吉田健一
  • Journal Title: 日本内科学会雑誌 Volume: 101 Pages: 1994-2001
  • NAID: 10031123099
  • Peer Reviewed
• [Presentation] Cohesin mutation (2014)
  • Author(s): Kenichi Yoshida
  • Organizer: Bone Marrow Failure Disease Scientific Symposium
  • Place of Presentation: Hilton Hotel Rockville (Rockville, U. S. A.)
  • Year and Date: 2014-03-27
  • Invited
• [Presentation] Whole exome sequencing reveals clonal evolution pattern and driver mu tations of relapsed pediatric AML (2013)
  • Author(s): Kenichi Yoshida
  • Organizer: 2013 ASH Annual Meeting and Exposition
  • Place of Presentation: Ernest N. Morial Convention Center (New Orleans, U. S. A.)
  • Year and Date: 2013-12-07
• [Presentation] ダウン症候群に合併する骨髄性腫瘍の遺伝学的基盤 (2013)
  • Author(s): 吉田健一
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2013-10-11
• [Presentation] Next-generation sequencing in hematological malignancies (2013)
  • Author(s): 吉田健一
  • Organizer: 第72回日本癌学会学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2013-10-05
  • Invited
• [Presentation] Genetic basis of myeloid leukemogenesis in Down syndrome (2013)
  • Author(s): Kenichi Yoshida
  • Organizer: 18^<th> Congress of EHA
  • Place of Presentation: Stockholmsmassan (Stock holm, Sweden)
  • Year and Date: 2013-06-15
• [Presentation] 血小板異常症 (2013)
  • Author(s): 吉田健一、國島伸治
  • Organizer: 第116回日本小児科学会学術集会
  • Place of Presentation: 広島市文化交流会館(広島市)
  • Year and Date: 2013-04-19
  • Invited
• [Presentation] Genetic basis of myeloid leukemogenesis in Down syndrome (2013)
  • Author(s): Kenichi Yoshida
  • Organizer: AACR Annual meeting 2013
  • Place of Presentation: Washington Convention Center (Washington D.C., U S.A)
  • Year and Date: 2013-04-09
• [Presentation] Genetic Basis of Myeloid Proliferation Related to Down Syndrome (2012)
  • Author(s): Kenichi Yoshida
  • Organizer: 2012 ASH Annual Meeting and Exposition
  • Place of Presentation: Georgia World Congress Center(Atlanta, U.S.A.)
  • Year and Date: 2012-12-10
• [Presentation] Whole genome and whole exome sequencing of congenital hematological disorders (2012)
  • Author(s): 吉田健一
  • Organizer: 第54回小児血液・がん学会学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)(招待講演)
  • Year and Date: 2012-12-02
• [Presentation] Whole genome and whole exome sequencing in MDS and leukemia (2012)
  • Author(s): 吉田健一
  • Organizer: 第54回小児血液・がん学会学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)(招待講演)
  • Year and Date: 2012-12-01
• [Presentation] Frequent pathway mutations of splicing machinery in myelodysplasia (2012)
  • Author(s): 吉田健一
  • Organizer: 第54回小児血液・がん学会学術集会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 2012-11-30
• [Presentation] Spectrum of gene mutations in myelodysplastic syndromes revealed by whole-exome sequencing (2012)
  • Author(s): 吉田健一
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都国際会館(京都市)
  • Year and Date: 2012-10-19
• [Presentation] Intratumor heterogeneity in myelodysplastic syndromes revealed by high-throughput sequencing (2012)
  • Author(s): 吉田健一
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都国際会館(京都市)
  • Year and Date: 2012-10-19
• [Presentation] Spectrum of gene mutations and intratumor heterogeneity inmyelodysplastic syndromes revealed by whole-exome and whole genome sequencing (2012)
  • Author(s): 吉田健一
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: 札幌市教育文化会館(札幌市)
  • Year and Date: 2012-09-21
• [Presentation] Spectrum of gene mutations and their intratumoral structurein myelodysplasia revealed by high-throughput sequencing (2012)
  • Author(s): Kenichi Yoshida
  • Organizer: 17th Congress of EHA
  • Place of Presentation: RAI Exhibition and Convention Centre (Amsterdam, the Netherland)
  • Year and Date: 2012-06-16