Comprehensive analysis of somatic and germline genomic alterations for atypical leukemia in children

• Project/Area Number: 17H04234
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Kato Motohiro 国立研究開発法人国立成育医療研究センター, 小児血液・腫瘍研究部, 診療部長 (40708690)
• Co-Investigator(Kenkyū-buntansha): 中林 一彦 国立研究開発法人国立成育医療研究センター, 周産期病態研究部, 室長 (10415557) ; 内山 徹 国立研究開発法人国立成育医療研究センター, 成育遺伝研究部, 室長 (10436107)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 癌

Outline of Final Research Achievements

The purpose of this project is to investigate underlying mechanism of clinical "outlier" among pediatric leukemia, using detailed genomic analysis.
As major findings of this project, we identified a novel fusion of RARB in acute promyelocytic leukemia which lacked typical translocation, and confirmed the pathogenic role for leukemogenesis. We also established a precise genotyping method of NUDT15 variants conferring sensitivity to mercaptopurine, a one of the key drugs for acute lymphoblastic leukemia.
Through these findings, we confirmed an importance of genomic analysis to understand clinical outlier.

Academic Significance and Societal Importance of the Research Achievements

非典型的な経過を取る小児白血病の病態には、それぞれ特有のゲノム異常が強くかかわっていることが確認された。ゲノム解析は標準的な検査では病態が把握できない、もしくは通常の臨床経過と異なる非典型例の病態を理解することにつながり、白血病の診療にあたってゲノム診断を実施することの重要性を検証する結果が得られた。

Research Products

• [Int'l Joint Research] St. Jude小児病院(米国)
• [Int'l Joint Research] シンガポール国立大学(シンガポール)
• [Int'l Joint Research] St. Jude小児病院(米国)
• [Journal Article] A novel KMT2A-ACTN2 fusion in infant B-cell acute lymphoblastic leukemia (2019)
  • Author(s): Masanori Yoshida、Kazuhiko Nakabayashi、Hiroko Ogata-Kawata、Tomoo Osumi、Shin-ichi Tsujimoto、Ryota Shirai、Kaoru Yoshida、Kohji Okamura、Kimikazu Matsumoto、Nobutaka Kiyokawa、Daisuke Tomizawa、Kenichiro Hata、Motohiro Kato
  • Journal Title: Pediatric Blood & Cancer Volume: in press (MPO27821) Issue: 8 Pages: 1-1
  • DOI: 10.1002/pbc.27821
  • Peer Reviewed / Open Access
• [Journal Article] Acute promyelocytic leukemia with a cryptic insertion of RARA into TBL1XR1 (2019)
  • Author(s): Osumi Tomoo、Watanabe Akihiro、Okamura Kohji、Nakabayashi Kazuhiko、Yoshida Masanori、Tsujimoto Shin‐ichi、Uchiyama Meri、Takahashi Hiroyuki、Tomizawa Daisuke、Hata Kenichiro、Kiyokawa Nobutaka、Kato Motohiro
  • Journal Title: Genes, Chromosomes and Cancer Volume: 58 Issue: 11 Pages: 820-823
  • DOI: 10.1002/gcc.22791
  • Peer Reviewed
• [Journal Article] Whole transcriptome sequencing reveals a KMT2A‐USP2 fusion in infant acute myeloid leukemia (2019)
  • Author(s): Ikeda Junji、Shiba Norio、Tsujimoto Shin‐ichi、Yoshida Masanori、Nakabayashi Kazuhiko、Ogata‐Kawata Hiroko、Okamura Kohji、Takeuchi Masanobu、Osumi Tomoo、Tomizawa Daisuke、Hata Kenichiro、Kiyokawa Nobutaka、Ito Shuichi、Kato Motohiro
  • Journal Title: Genes, Chromosomes and Cancer Volume: in press Issue: 9 Pages: 1-1
  • DOI: 10.1002/gcc.22751
  • Peer Reviewed / Open Access
• [Journal Article] RecurrentRARBTranslocations in Acute Promyelocytic Leukemia LackingRARATranslocation (2018)
  • Author(s): Osumi Tomoo、Tsujimoto Shin-ichi、Tamura Moe、Uchiyama Meri、Nakabayashi Kazuhiko、、Takita Junko（22ｔｈ）、Inukai Takeshi、Ogawa Seishi、Kitamura Toshio、Matsumoto Kimikazu、Hata Kenichiro、Kiyokawa Nobutaka、Goyama Susumu、Kato Motohiro
  • Journal Title: Cancer Research Volume: 78 Issue: 16 Pages: 4452-4458
  • DOI: 10.1158/0008-5472.can-18-0840
  • Peer Reviewed
• [Journal Article] Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms (2018)
  • Author(s): Tsujimoto S, Osumi T, Uchiyama M, Shirai R, Moriyama T, Nishii R, Yamada Y, Kudo K, Sekiguchi M, Arakawa Y, Yoshida M, Uchiyama T, Terui K, Ito S, Koh K, Takita J, Ito E, Tomizawa D, Manabe A, Kiyokawa N, Yang JJ, Kato M.
  • Journal Title: Leukemia Volume: 32 Issue: 12 Pages: 2710-2714
  • DOI: 10.1038/s41375-018-0190-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Somatic MECOM mosaicism in a patient with congenital bone marrow failure without a radial abnormality (2018)
  • Author(s): Osumi Tomoo、Tsujimoto Shin-ichi、Nakabayashi Kazuhiko、Taniguchi Maki、Shirai Ryota、Yoshida Masanori、Uchiyama Toru、Nagasawa Junko、Goyama Susumu、Yoshioka Takako、Tomizawa Daisuke、Kurokawa Mineo、Matsubara Yoichi、Kiyokawa Nobutaka、Matsumoto Kimikazu、Hata Kenichiro、Kato Motohiro
  • Journal Title: Pediatric Blood & Cancer Volume: 65 Issue: 6
  • DOI: 10.1002/pbc.26959
  • Peer Reviewed
• [Journal Article] Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. (2017)
  • Author(s): Seki M, Kimura S, Isobe T, Yoshida K, (13 authors), Masuda K, Kawamoto H, Ohki K, Kato M, Arakawa Y, Koh K, Hanada R, Moritake H, Akiyama M, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi Y, Takagi M, Manabe A, Ohara A, Horibe K, Sanada M, Iwama A, Mano H, Miyano S, Ogawa S, Takita J
  • Journal Title: Nature Genetics Volume: 49 Issue: 8 Pages: 1274-1281
  • DOI: 10.1038/ng.3900
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Cryptic NUP214-ABL1 Fusion in B-cell Precursor Acute Lymphoblastic Leukemia. (2017)
  • Author(s): Tsujimoto SI, Nakano Y, Osumi T, Okada K, Ouchi-Uchiyama M, Kataoka K, Fujii Y, Ohki K, Seki M, Tamagawa N, Takita J, Ogawa S, Kiyokawa N, Hara J, Kato M.
  • Journal Title: J Pediatr Hematol Oncol. Volume: － Issue: 6 Pages: 1-1
  • DOI: 10.1097/mph.0000000000001007
  • Peer Reviewed / Open Access
• [Journal Article] Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic KRAS. (2017)
  • Author(s): Osumi T, Kato M, Ouchi-Uchiyama M, Tomizawa D, Kataoka K, Fujii Y, Seki M, Takita J, Ogawa S, Uchiyama T, Ohki K, Kiyokawa N.
  • Journal Title: Pediatr Blood Cancer. Pediatr Blood Cancer. Volume: 64(9) Issue: 9
  • DOI: 10.1002/pbc.26496
  • Peer Reviewed / Open Access
• [Presentation] Recent updates of NUDT15 (2019)
  • Author(s): Kato M
  • Organizer: 1st Annual Meeting of the European Society for Pediatric Oncology
  • Int'l Joint Research
• [Presentation] NUDT15 Variants Confer High Incidence of Secondary Malignancies of ALL in Children (2019)
  • Author(s): Yoshida M
  • Organizer: 61th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] 急性リンパ性白血病の治療の進歩 (2019)
  • Author(s): 加藤元博
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] Germline Genetic Predisposition to Secondary Malignant Neoplasms in Children (2018)
  • Author(s): Yoshida M et al.
  • Organizer: The 50th Congress of International Society of Pediatric Oncology
  • Int'l Joint Research
• [Presentation] RARB translocations in acute promyelocytic leukemia without RARA translocation. (2017)
  • Author(s): Kato M et al.
  • Organizer: The 59th Annual meeting of the American Society of Hematology
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 新規なポリヌクレオチド及びその利用 (2017)
  • Inventor(s): 加藤元博
  • Industrial Property Rights Holder: 加藤元博
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2017-211205
  • Filing Date: 2017