Molecular analysis of pediatric MDS/AML

• Project/Area Number: 15K09653
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Okayama University
• Principal Investigator: Shimada Akira 岡山大学, 大学病院, 准教授 (70391836)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2017: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 骨髄異形成症候群 / 急性骨髄性白血病 / がん抑制遺伝子 / メチル化 / RAEBT / RAEB / 遺伝子変異 / epigenetic変化 / AML

Outline of Final Research Achievements

Epigenetic status of the promotor region on tumor suppressor gened (TSGs) in pediatric myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) are still remains unknown. We analyzed the aberrant methylation of promotor region of 25 TSGs in pediatric 7 low grade MDS, 4 advanced MDS and 22 AML patients by FAB classification by MS-MLPA method. Total 12/22(54.5%) patients had more than one methylated TSGs (number of methylated TSGs was 0-5 in each patient, median 1). More than 20% of patients had methylated TSGs including CDKN2B, CADM1, CDH13 and ESR1. Especially, all (4/4) t(8;21) patients had CDH13 methylation, 3/4 (75%) patients with inv(16) had ESR1 methylation and normal karyotype did not. Complete remission samples, and low grade MDS samples were not methylated. All advanced MDS patients had 1 or 2 methylated TSGs. In this study, many genes related to epigenetic modification such as ASXL1, TET2 and EZH2 were not mutated. Aberrant methylation was started in advanced MDS.

Academic Significance and Societal Importance of the Research Achievements

成人と比較して、小児の骨髄異形成症候群（MDS)/急性骨髄性白血病（AML）でもがん抑制遺伝子のメチル化がみられたことは、今後小児でも抗メチル化薬の応用が期待できる。また成人とは異なりepigenetic modifier遺伝子の変異はみられなかったことは重要と考えられる。

Research Products

• [Journal Article] Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia (2019)
  • Author(s): Tamefusa K, Fukutake K, Ishida H, Tamura A, Endo M, Hamamoto K, Koga Y, Yamada M, Kanamitsu K, Fujiwara K, Washio K, Shimada A.
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 2 Pages: 99-105
  • DOI: 10.11406/rinketsu.60.99
  • NAID: 130007607737
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Clinical and biological features of paediatric acute myeloid leukaemia (AML) with primary induction failure in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. (2019)
  • Author(s): Miyamura T, Moritake H, Nakayama H, Tanaka S, Tomizawa D, Shiba N, Saito AM, Tawa A, Shimada A, Iwamoto S, Hayashi Y, Koike T, Horibe K, Manabe A, Mizutani S, Taga T, Adachi S.
  • Journal Title: Br J Haematol. Volume: 19 Issue: 2 Pages: 284-288
  • DOI: 10.1111/bjh.15799
  • Peer Reviewed
• [Journal Article] Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia (2018)
  • Author(s): Yagi K, Shimada A, Sendo T
  • Journal Title: European Journal of Pharmacology Volume: 825 Pages: 28-33
  • DOI: 10.1016/j.ejphar.2018.02.022
  • Peer Reviewed
• [Journal Article] Risk-stratified therapy for children with FLT3-ITD-positive acute myeloid leukemia: results from the JPLSG AML-05 study. (2018)
  • Author(s): Shimada A, Iijima-Yamashita Y, Tawa A, Tomizawa D, Yamada M, Norio S, Watanabe T, Taga T, Iwamoto S, Terui K, Moritake H, Kinoshita A, Takahashi H, Nakayama H, Koh K, Goto H, Kosaka Y, Saito AM, Kiyokawa N, Horibe K, Hara Y, Oki K, Hayashi Y, Tanaka S, Adachi S.
  • Journal Title: Int J Hematol. Volume: 107(5) Issue: 5 Pages: 586-595
  • DOI: 10.1007/s12185-017-2395-x
  • Peer Reviewed
• [Journal Article] Five Cases of Pediatric-Onset Bechet’s disease complicated with Myelodysplastic Syndrome (2017)
  • Author(s): Kanamitsu K, Shimada A, Nishiuchi R, Shigemura T, Nakazawa Y, Koike K, Kodama Y, Shinkoda Y, Kawano Y, Yasui K, Sasaki K, Kajiwara R, Tsukahara H, Manabe A.
  • Journal Title: International Journal of Hematology Volume: 105 Issue: 3 Pages: 377-382
  • DOI: 10.1007/s12185-016-2127-7
  • Peer Reviewed
• [Journal Article] Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. (2016)
  • Author(s): Shiba N, Yoshida K, Shiraishi Y, Okuno Y, Yamato G, Hara Y, Nagata Y, Chiba K, Tanaka H, Terui K, Kato M, Park MJ, Ohki K, Shimada A, Takita J, Tomizawa D, Kudo K, Arakawa H, Adachi S, Taga T, Tawa A, Ito E, Horibe K, Sanada M, Miyano S, Ogawa S, Hayashi Y.
  • Journal Title: Br J Haematol. Volume: 175 Issue: 3 Pages: 476-489
  • DOI: 10.1111/bjh.14247
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Relapsed AML patient with inv(16) harboring a low FLT3-ITD allelic burden and KIT mutations (2016)
  • Author(s): Yamada A., Moritake H., Kinoshita M., Sawa D., Kamimura S., Iwamoto S., Yamashita Y., Inagaki J., Takahashi T., Shimada A., Obara M., Nunoi H.
  • Journal Title: Pediatric Int. Volume: 58 Issue: 9 Pages: 905-908
  • DOI: 10.1111/ped.13010
  • Peer Reviewed
• [Presentation] Aberrant Methylation of Tumor Suppressor Genes in Pediatric Myelodysplastic Syndrome / Acute Myeloid Leukemia (2018)
  • Author(s): Akira Shimada, Hirotaka Kanzaki, Hisashi Ishida, Takehiro Matsubara, Michinori Aoe
  • Organizer: American Association of Cancer Research
  • Int'l Joint Research
• [Presentation] キメラスクリーニングによる小児急性巨核芽球性白血病の予後解析 (2018)
  • Author(s): 爲房 宏輔, 福武 功志郎, 石田 悠志, 田村 彰広, 遠藤 幹也, 浜本 和子, 古賀 友紀, 山田 睦子, 金光 喜一郎, 藤原 かおり, 鷲尾 佳奈, 嶋田 明
  • Organizer: 日本血液学会中四国地方会
• [Presentation] 小児advanced MDSの治療成績について (2018)
  • Author(s): 嶋田 明
  • Organizer: 小児AA/MDS研究会
• [Presentation] Aberrant Methylation of Tumor Suppressor Genes in Pediatric Myelodysplastic Syndrome / Acute Myeloid Leukemia (2018)
  • Author(s): Akira Shimada, Hirotaka Kanzaki, Hisashi Ishida, Takehiro Matsubara, Michinori Aoe
  • Organizer: American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] Pediatric AML with genetic alterations (2016)
  • Author(s): A. SHIMADA
  • Organizer: 日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-12
  • Invited
• [Presentation] The challenge of risk-reclassification of Pediatric AML with FLT3 wild type; JPLSG AML05 study (2016)
  • Author(s): A. SHIMADA
  • Organizer: International BFM Annual meeting
  • Place of Presentation: アテネ
  • Year and Date: 2016-04-22
  • Int'l Joint Research / Invited
• [Presentation] AML-oriented chemotherapy is effective for RAEB and RAEBT in children (2015)
  • Author(s): Akira Shimada, Akitoshi Kinoshita, Atsushi Manabe, Daisuke Hasegawa, Miharu Yabe, Hayato Miyachi, Hiromichi Matsushita, Tomohiko Taki, Masami Inoue, Asahito Hama, Daiichiro Hasegawa, Masafumi Ito, Akio Tawa, Seiji Kojima, Souich Adachi
  • Organizer: EWOG-MDS
  • Place of Presentation: Aarhus, Denmark
  • Year and Date: 2015-10-01
  • Int'l Joint Research
• [Presentation] Retrospective Analysis of Infant AML in Japan from 2000-2010 (2015)
  • Author(s): Akira Shimada, Daisuke Tomizawa, Atsushi Ogawa, Takashi Taga, Toshihiko Imamura, Akio Tawa, Keizo Horibe, Tomohiko Taki, Yasuhide Hayashi, Souichi Adachi
  • Organizer: International BFM Annual meeting
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-05-08
  • Int'l Joint Research / Invited
• [Book] 小児科【Down症を見つめる】 血液疾患 (2019)
  • Author(s): 嶋田 明
  • Total Pages: 4
  • Publisher: 金原出版
• [Book] 小児内科増刊号2016 (2016)
  • Author(s): 嶋田 明
  • Total Pages: 1228
  • Publisher: 東京医学社