Comprehensive genetic analysis of pediatric acute myeloid leukemia

• Project/Area Number: 25893028
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: Gunma University
• Principal Investigator: SHIBA NORIO 群馬大学, 医学部附属病院, 助教 (50600615)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PRDM16 / AML / 小児 / FLT3-ITD / 急性骨髄性白血病 / 遺伝子発現 / 遺伝子変異解析 / 治療層別化

Outline of Final Research Achievements

The genetic alterations responsible for adverse outcomes in patients with pediatric acute myeloid leukemia (AML) remain obscure. Recent reports described NUP98-NSD1 fusion as an adverse AML prognostic marker and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harboring NUP98-NSD1 fusion. In 369 pediatric patients with de novo AML from the Japanese AML-05 clinical trial, PRDM16 gene expression levels were measured via real-time PCR, and correlations between these and other genetic alterations were investigated to clarify the clinical significance and prognostic impact. Overall, 84 of 369 patients (23%) exhibited PRDM16 overexpression. The overall (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than those among patients with low PRDM16 expression irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was especially useful for stratifying FLT3-ITD-positive patients with AML.

Research Products

• [Journal Article] 次世代シーケンサーによる小児血液、腫瘍疾患における研究の進展 急性骨髄性白血病における遺伝子異常 (2015)
  • Author(s): 柴 徳生
  • Journal Title: 日本小児血液がん学会雑誌 Volume: 51 Pages: 397-405
  • Peer Reviewed
• [Journal Article] High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML. (2015)
  • Author(s): Jo A, Mitani S, Shiba N, Hayashi Y, Hara Y, Takahashi H, Tsukimoto I, Tawa A, Horibe K, Tomizawa D, Taga T, Adachi S, Yoshida T, Ichikawa H
  • Journal Title: Leukemia Volume: 29 Issue: 5 Pages: 1067-1083
  • DOI: 10.1038/leu.2015.5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 癌になりやすい体質，胚細胞変異とモザイク (2015)
  • Author(s): 柴 徳生
  • Journal Title: 小児外科 Volume: 47 Pages: 118-122
  • Peer Reviewed
• [Journal Article] CSF3R and CALR mutations in paediatric myeloid disorders and the association of CSF3R mutations with translocations, including t(8; 21). (2015)
  • Author(s): Sano H, Ohki K, Park MJ, Shiba N, et al.
  • Journal Title: Br J Haematol. Volume: Epub ahead of print Issue: 3 Pages: 319-397
  • DOI: 10.1111/bjh.13439
  • Peer Reviewed / Open Access
• [Journal Article] EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia. (2014)
  • Author(s): Matsuo H, Kajihara M, Tomizawa D, Watanabe T, Saito AM, Fujimoto J, Horibe K, Kodama K, Tokumasu M, Itoh H, Nakayama H, Kinoshita A, Taga T, Tawa A, Taki T, Shiba N, Ohki K, Hayashi Y, Yamashita Y, Shimada A, Tanaka S, Adachi S.
  • Journal Title: Haematologica Volume: 99 Issue: 11 Pages: 225-227
  • DOI: 10.3324/haematol.2014.107128
  • Peer Reviewed / Open Access
• [Journal Article] NUP98-NSD1 related gene expression signature is strongly associated with a poor prognosis in pediatric acute myeloid leukemia: a study of the Japanese Childhood AML Cooperative Study Group Cooperative Study Group (2013)
  • Author(s): Shiba N, Ichikawa H, Taki T, Park M, Jo A, Mitani S, Shimada A, Sotomatsu M, Arakawa H, Tabuchi K, Adachi S, Tawa A, Horibe K, Tsuchida M, Hanada R, Tsukimoto I, Hayashi Y
  • Journal Title: Genes Chromosomes Cancer Volume: 52 Issue: 7 Pages: 683-693
  • DOI: 10.1002/gcc.22064
  • Peer Reviewed
• [Presentation] PRDM16 (2014)
  • Author(s): Norio Shiba
  • Organizer: アメリカ血液学会（ASH）
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2014-12-09 – 2014-12-12
• [Presentation] AML (2014)
  • Author(s): Norio Shiba
  • Organizer: 日本小児血液がん学会
  • Place of Presentation: 岡山
  • Year and Date: 2014-11-28 – 2014-11-30
• [Presentation] AML (2014)
  • Author(s): Norio Shiba
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 小児急性骨髄性白血病における分子生物学的背景を用いた新たな治療層別化への試み (2014)
  • Author(s): 柴 徳生
  • Organizer: 日本小児科学会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-13 – 2014-04-15
• [Presentation] 小児AMLにおける分子生物学的背景を用いた新たな治療層別化への試み (2014)
  • Author(s): Norio Shiba et al.
  • Organizer: 第117回日本小児科学会
  • Place of Presentation: 名古屋
• [Presentation] Whole-Exome Resequencing Identifies Somatic Mutations of BCOR and BCORL1 Transcriptional Corepressor Genes and Major Cohesin Complex Component Genes in Pediatric AML (2013)
  • Author(s): Norio Shiba et al.
  • Organizer: The 55th ASH
  • Place of Presentation: ニューオリンズ
• [Presentation] 全エクソーム解析による小児AML の新規原因遺伝子の同定 (2013)
  • Author(s): Norio Shiba et al.
  • Organizer: 第55回日本小児血液がん学会
  • Place of Presentation: 福岡
• [Presentation] Whole-exome resequencing identifies somatic mutations of BCORL1 and major cohesin complex component genes in pediatric AML (2013)
  • Author(s): Norio Shiba et al.
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌
• [Presentation] NUP98-NSD1 gene fusiontranslocation is a strong poor prognostic factor in pediatric AML (2013)
  • Author(s): Yusuke Hara, Norio Shiba et al.
  • Organizer: The 45th International Society of Paediatric Oncology
  • Place of Presentation: 香港