Identification of novel prognostic factors genome-wide DNA methylation analysis in pediatric acute myeloid leukemia.

• Project/Area Number: 20K17414
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Gunma University (2022); Gunma Institute of Public Health and Environmental Sciences (2020-2021)
• Principal Investigator: Yamato Genki 群馬大学, 医学部附属病院, 助教 (90825720)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: DNAメチル化 / 小児急性骨髄性白血病 / 小児 / 急性骨髄性白血病

Outline of Research at the Start

初年度は研究準備、そして主にDNAメチル化解析を中心に行う。可能な限り統計解析を進めていきながら、臨床データとのデータ比較を行っていく。
次年度以降は統計解析を更に進めていく。具体的には統計解析ソフト“R”を使用したunsupervised clusteringを行い、DNAメチル化パターンと臨床データ、分子生物学的背景、予後との関係を明らかにすることを目的とする。その上で興味深いDNAメチル化パターンが確認された場合には細胞株を使用した薬剤試験なども検討していく。

Outline of Final Research Achievements

Although the long-term survival rate of pediatric acute myeloid leukemia (AML) has increased to 60-70% with stratified therapy based on molecular abnormalities and response to therapy, the prognosis is still not good. Recently, DNA methylation has begun to attract attention as a new biomarker for AML. To clarify the relationship between DNA methylation patterns and clinical presentation, molecular biological background, and prognosis in pediatric AML, we performed DNA methylation analysis on 64 patients enrolled in the AML-05 clinical trial.
We found a strong correlation between DNA methylation patterns and molecular background, and identified a group of patients characterized by high DNA methylation patterns as having a particularly poor prognosis.

Academic Significance and Societal Importance of the Research Achievements

現在がん領域においては次世代シーケンサーを使用した網羅的な解析が主流となってきたが、小児急性骨髄性白血病(AML)の40%近くはまだ予後を層別するバイオマーカーが見つからない状態であり、治療決定の根拠として新たなバイオマーカーの同定は必要不可欠となってきている。本研究ではDNAメチル化パターンがAMLの分子生物学的特徴と相関し、更には予後と密接に関連することを報告した。この成果は今後小児AMLにおいて治療層別化のための重要なバイオマーカーとなる可能性を示しており、より適切なリスク層別を行うことで小児AMLの予後を改善する可能性を示した重要な結果である。

Research Products

• [Journal Article] Genome-wide DNA Methylation Analysis in Pediatric Acute Myeloid Leukemia. (2022)
  • Author(s): Yamato G, Kawai T, Shiba N, Ikeda J, Hara Y, Ohki K, Tsujimoto SI, Kaburagi T, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Taga T, Horibe K, Ogawa S, Hata K, Hayashi Y.
  • Journal Title: Blood advances Volume: in press Issue: 11 Pages: 3207-3219
  • DOI: 10.1182/bloodadvances.2021005381
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome (2021)
  • Author(s): Yamato G, Deguchi T, Terui K, Toki T, Watanabe T, Imaizumi T, Hama A, Iwamoto S, Hasegawa D, Ueda T, Yokosuka T, Tanaka S, Yanagisawa R, Koh K, Saito AM, Horibe K, Hayashi Y, Adachi S, Mizutani S, Taga T, Ito E, Watanabe K, Muramatsu H.
  • Journal Title: Leukemia. Volume: 35 Issue: 5 Pages: 1480-1484
  • DOI: 10.1038/s41375-021-01171-y
  • Peer Reviewed
• [Journal Article] Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution. (2021)
  • Author(s): Yamato G, Park MJ, Hayashi Y, et al.
  • Journal Title: Int J Hematol. Volume: 113 Issue: 5 Pages: 662-667
  • DOI: 10.1007/s12185-020-03066-7
  • Peer Reviewed
• [Journal Article] Clinical significance of RAS pathway alterations in pediatric acute myeloid leukemia. (2021)
  • Author(s): Kaburagi T, Yamato G, Shiba N, Yoshida K, Hara Y, Tabuchi K, Shiraishi Y,Ohki K, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Taki T, Kiyokawa N, Tomizawa D, Horibe K, Miyano S, Taga T, Adachi S, Ogawa S, Hayashi Y.
  • Journal Title: Haematologica Volume: － Issue: 3 Pages: 583-592
  • DOI: 10.3324/haematol.2020.269431
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Droplet digital polymerase chain reaction assay for the detection of the minor clone of KIT D816V in paediatric acute myeloid leukaemia especially showing RUNX1-RUNX1T1 transcripts. (2021)
  • Author(s): Sasaki K, Tsujimoto S, Miyake M, Uchiyama Y, Ikeda J, Yoshitomi M, Shimosato Y, Tokumasu M, Matsuo H, Yoshida K, Ohki K, Kaburagi T, Yamato G, Hara Y, Takeuchi M, Kinoshita A, Tomizawa D, Taga T, Adachi S, Tawa A, Horibe K, Hayashi Y, Matsumoto N, Ito S, Shiba N.
  • Journal Title: British Journal of Haematology Volume: 194(2) Issue: 2 Pages: 414-422
  • DOI: 10.1111/bjh.17569
  • Peer Reviewed
• [Journal Article] Sudden unexpected death caused by infantile acute lymphoblastic leukaemia (2021)
  • Author(s): Morota Kei、Shimizu Mariko、Sugitate Ryo、Ide Munenori、Yamato Genki、Tomizawa Daisuke、Muramatsu Kazuhiro、Matsui Atsushi
  • Journal Title: Oxford Medical Case Reports Volume: 2021 Issue: 8
  • DOI: 10.1093/omcr/omab073
  • Peer Reviewed
• [Presentation] 小児急性骨髄性白血病における全ゲノムDNAメチル化解析 -The JCCG-JPLSG AML-05 study- (2021)
  • Author(s): 大和玄季, 河合智子, 柴 徳生, 原勇介, 大木健太郎, 鏑木多映子, 吉田健一, 白石友一, 宮野悟, 清河信敬, 富澤 大輔 , 嶋田明, 外松学, 荒川 浩一 , 足立壮一, 多賀崇 , 堀部敬三, 小川誠司, 秦健一郎, 林泰秀
  • Organizer: 第83回日本血液学会
• [Presentation] 急性骨髄性白血病におけるDNAメチル化の意義と層別化への有用性 Significance and usefulness of DNA Methylation Analysis for risk stratification in Acute Myeloid Leukemia (2021)
  • Author(s): 大和玄季
  • Organizer: 第63回日本小児血液・がん学会学術集会
• [Presentation] 一過性骨髄異常増殖症患者151例におけるサイトカイン解析: JCCG JPLSG TAM-10 study (2021)
  • Author(s): 大和玄季, 朴明子、嶋田明、柴徳生、山田佳之、照井君典、村松秀城、渡邉健一郎、林泰秀
  • Organizer: 第63回日本小児血液・がん学会学術集会
• [Presentation] Cytokine analysis in 154 patients with transient abnormal myelopoiesis: JCCG JPLSG TAM-10 clinical study (2021)
  • Author(s): Yamato G, Park MJ, Shimada A, Shiba N, Yamada Y, Terui K, Ito E, Muramatsu H, Watanabe K, Hayashi Y,
  • Organizer: 63rd American Society of Hematology Annual Meeting