Integrated analysis of clonal evolution at early stage of myelodysplastic syndrome.

• Project/Area Number: 26893127
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Kyoto University
• Principal Investigator: Nagata Yasunobu 京都大学, 医学(系)研究科(研究院), 助教 (90739575)
• Project Period (FY): 2014-08-29 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄異形成症候群 / 全エクソンシークエンス / 再生不良性貧血 / ゲノム / 癌

Outline of Final Research Achievements

We performed whole exome sequencing of 22 patients who diagnosed aplastic anemia and progressed myelodysplatic syndromes, which identified 66 mutations. They included not only PIGA which was already reported in aplastic anemia but also BCOR and BCORL1 which were not. Given analysis of different time points of several years from diagnosis, a tiny clone with mutations increased and acquired novel genetic alterations such as SETBP1 mutations, which related to advanced disease. In conclusion, variation of complicated clone structure informs the evolution from aplastic anemia to myelodysplatic syndrome.

Research Products

• [Journal Article] Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia. (2016)
  • Author(s): Wakita S, Yamaguchi H, Ueki T, Usuki K, Kurosawa S, Kobayashi Y, Kawata E, Tajika K, Gomi S, Koizumi M, Fujiwara Y, Yui S, Fukunaga K, Ryotokuji T, Hirakawa T, Arai K, Kitano T, Kosaka F, Tamai H, Nakayama K, Fukuda T, Inokuchi K
  • Journal Title: Leukemia Volume: 60 Issue: 22 Pages: 545-554
  • DOI: 10.1182/blood-2015-05-646240
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Variegated RHOA mutations in adult T-cell leukemia/lymphoma (2016)
  • Author(s): Nagata Y, Kontani K, Enami T, Kataoka K, Ishii R, Totoki Y, Kataoka TR, Hirata M, Aoki K, Nakano K, Kitanaka A, Sakata-Yanagimoto M, Egami S, Shiraishi Y, Chiba K, Tanaka H, Shiozawa Y, Yoshizato T, (9名), Miyano S, Nureki O, Shibata T, Haga H, Shimoda K, Katada T, Chiba S, Watanabe T, Ogawa S
  • Journal Title: Blood Volume: 127 Issue: 5 Pages: 596-604
  • DOI: 10.1182/blood-2015-06-644948
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] BRCC3 mutations in myeloid neoplasms. (2015)
  • Author(s): Huang D, Nagata Y, Grossmann V, Radivoyevitch T, Yoshida K, Sekeres MA, Oakley K, Nguyen N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Miyano S, Haferlach C, Kern W, Haferlach T, Du Y, Ogawa S, Makishima H.
  • Journal Title: Haematologica Volume: 100(8) Pages: 1051-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. (2015)
  • Author(s): Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu CO, Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa Y, Okuno Y, Chiba K, Tanaka H, Nagata Y, Katagiri T, Kon A, Sanada M, Scheinberg P, Miyano S, Maciejewski JP, Nakao S, Young NS, Ogawa S.
  • Journal Title: N Engl J Med. Volume: 373 Issue: 1 Pages: 35-47
  • DOI: 10.1056/nejmoa1414799
  • NAID: 120005623244
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated molecular analysis of adult T cell leukemia/lymphoma. (2015)
  • Author(s): Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, et al.
  • Journal Title: Nat Genet. Volume: 47(11) Issue: 11 Pages: 1304-15
  • DOI: 10.1038/ng.3415
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genomon ITDetector: a tool for somatic internal tandem duplication detection from cancer genome sequencing data. (2015)
  • Author(s): Chiba K, Shiraishi Y, Nagata Y, Yoshida K, Imoto S, Ogawa S, Miyano S.
  • Journal Title: Bioinformatics Volume: 31 Issue: 1 Pages: 116-118
  • DOI: 10.1093/bioinformatics/btu593
  • Peer Reviewed
• [Journal Article] A robust molecular pattern for myelodysplastic syndromes in two independent cohorts investigated by next-generation sequencing can be revealed by comparative bioinformatic analyses. (2014)
  • Author(s): Rose D, Kohlmann A, Nagata Y, Ogawa S, Haferlach C, Kern W, Schnittger S, Haferlach T.
  • Journal Title: British Journal of Haematology Volume: 167(2) Issue: 2 Pages: 278-281
  • DOI: 10.1111/bjh.12971
  • Peer Reviewed
• [Journal Article] Expressional changes of genes and miRNA in common megakaryocyte-erythroid progenitors from lower-risk myelodysplastic syndrome. (2014)
  • Author(s): Maki K, Sasaki K, Nagata Y, Nagasawa F, Nakamura Y, Ogawa S, Mitani K.
  • Journal Title: International Journal of Hematology Volume: 46(8) Issue: 4 Pages: 361-369
  • DOI: 10.1007/s12185-014-1639-2
  • Peer Reviewed
• [Presentation] Landscape of DNA methylation and genetic profiles in 288 patients with myelodysplastic syndromes (2015)
  • Author(s): Yasunobu Nagata
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2015-10-18
• [Presentation] 骨髄異形成症候群（MDS)288例における網羅的DNAメチル化解析と標的遺伝子異常との統合解析 (2015)
  • Author(s): Yasunobu Nagata
  • Organizer: 第74回日本癌学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
• [Presentation] Novel Biological Effects and Distinct Patterns of Rhoa Mutations in Adult T-Cell Leukemia/Lymphoma and Angioimmunoblastic T Cell Lymphoma (2014)
  • Author(s): Yasunobu Nagata
  • Organizer: 56th ASH Annual Meeting and Exposition
  • Place of Presentation: ニューオリンズ
  • Year and Date: 2014-12-07
• [Presentation] Distinct Pattrens of RHOA mutations in Adult Tcell Leukemia/Lymphoma and Per ipheral T-Cell Lymphomas (2014)
  • Author(s): Yasunobu Nagata
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2014-11-01
• [Presentation] Novel distributions and biological effects of RHOA mutations In Adult T-cell Leukemia/Lymphoma and other PTCLs (2014)
  • Author(s): Yasunobu Nagata
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-26