Comprehensive genetic analysis in pediatric acute myeloid leukemia to elucidate the clinical significance of genes on chromosome 7.

• Project/Area Number: 21K20937
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0904:Internal medicine of the bio-information integration and related fields
• Research Institution: Gunma Institute of Public Health and Environmental Sciences
• Principal Investigator: Kaburagi Taeko 群馬県衛生環境研究所, 研究企画係, 研究員 (20907084)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 小児 / 急性骨髄性白血病 / パネルシーケンス / 7番染色体 / KMT2C / ７番染色体

Outline of Research at the Start

小児急性骨髄性白血病(AML)の長期生存率は、様々な分子生物学的異常と予後との関連が明らかとなり、層別化治療が進んだことで向上している。一方、既知の予後因子を有さず中間リスク群と扱われる一部には再発難治例が存在し、より詳細な予後因子の解明が求められている。本研究では予後不良因子であるmonosomy 7に着目し、7番染色体上のいずれかの遺伝子異常が小児AMLにおいて重要な予後因子となる可能性を考え、日本小児白血病リンパ腫研究グループAML-05研究症例に対してパネルシーケンスを施行し、臨床的意義のある遺伝子の同定を目指すとともに、それらの臨床的特徴や他の分子生物学的異常との関連を検証する。

Outline of Final Research Achievements

Identification of novel prognostic factors is urgently needed to improve the prognosis of pediatric acute myeloid leukemia (AML). We focused on monosomy 7 and deletion of the long arm of chromosome 7[del(7q)], which are representative chromosomal abnormalities in AML, and performed mutation analysis and copy number analysis of genes on chromosome 7 using next-generation sequencing to verify their clinical significance. Monosomy 7 was significantly associated with poor prognosis, while del(7q) was not associated with prognosis. MECOM high expression was significantly more common in monosomy 7 but not in del(7q), suggesting that monosomy 7 and del(7q) have different molecular biological backgrounds. As for genetic mutations on the long arm of chromosome 7, patients with KMT2C mutations had a significantly poorer prognosis, suggesting that KMT2C mutations may be an important prognostic factor in pediatric AML.

Academic Significance and Societal Importance of the Research Achievements

小児急性骨髄性白血病(AML)において、これまでもmonosomy 7と7番染色体長腕欠損[del(7q)]は着目され、それらの共通欠失領域に重要な遺伝子が存在することが考えられてきたが、いまだに責任遺伝子の同定には至っていない。本研究ではmonosomy 7と7番染色体長腕欠損[del(7q)]の予後が異なり、背景としてmonosomy 7にはMECOM高発現の合併が多い一方、del(7q)には少ないなど、分子生物学的背景が大きく異なることが考えられた。これらは7番染色体上にはMonosomy 7やdel(7q)の共通欠失領域以外に重要な因子がある可能性を示唆する新たな知見と考えられた。

Research Products

• [Journal Article] UBTF-internal tandem duplication as a novel poor prognostic factor in pediatric acute myeloid leukemia. (2023)
  • Author(s): Kaburagi T, Shiba N, Yamato G, Yoshida K, Tabuchi K, Ohki K, Ishikita E, Hara Y, Shiraishi Y, Kawasaki H, Sotomatsu M, Takizawa T, Taki T, Kiyokawa N, Tomizawa D, Horibe K, Miyano S, Taga T, Adachi S, Ogawa S, Hayashi Y.
  • Journal Title: Genes Chromosomes Cancer Volume: 62 Issue: 4 Pages: 202-209
  • DOI: 10.1002/gcc.23110
  • Peer Reviewed
• [Journal Article] TP53 and RB1 alterations characterize poor prognostic subgroups in pediatric acute myeloid leukemia. (2023)
  • Author(s): Hara Y, Shiba N, Yoshida K, Yamato G, Kaburagi T, Shiraishi Y, Ohki K, Shiozawa Y, Kawamura M, Kawasaki H, Sotomatsu M, Takizawa T, Matsuo H, Shimada A, Kiyokawa N, Tomizawa D, Taga T, Ito E, Horibe K, Miyano S, Adachi S, Taki T, Ogawa S, Hayashi Y.
  • Journal Title: Genes Chromosomes Cancer Volume: 62 Issue: 7 Pages: 412-422
  • DOI: 10.1002/gcc.23147
  • Peer Reviewed
• [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] 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] 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
• [Presentation] UBTF-ITDは小児急性骨髄性白血病の予後因子である (2022)
  • Author(s): 鏑木多映子, 大和玄季, 柴徳生, 吉田健一, 石北悦子, 原勇介, 白石友一, 大木健太郎, 河崎裕英, 外松学, 滝沢琢己, 滝智彦, 清河信敬, 富澤大輔, 堀部敬三, 宮野悟, 多賀崇, 足立壮一, 小川誠司, 林泰秀
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] DNAメチル化パターンによるKMT2A-MLLT3陽性小児急性骨髄性白血病患者の予後予測 (2022)
  • Author(s): 3．大和玄季, 河合智子, 柴 徳生, 原勇介, 大木健太郎, 鏑木多映子, 石北悦子, 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, 滝沢琢己 , 足立壮一, 多賀崇 , 堀部敬三, 小川誠司, 秦健一郎, 林泰秀
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Prognosis of pediatric acute myeloid leukemia with KMT2A-MLLT3 according to DNA methylation patterns: JCCG JPLSG AML-05 study. (2022)
  • Author(s): Yamato G, Kawai T, Shiba N, Hara Y, Ohki K, Kaburagi T, Ishikita E, Kawasaki H, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Takizawa T, Adachi S, Taga T, Horibe K, Ogawa S, Hata K, Hayashi Y.
  • Organizer: 64th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] 小児急性骨髄性白血病における7番染色体上の遺伝子異常と臨床的意義 (2021)
  • Author(s): 鏑木多映子、大和玄季、柴徳生、吉田健一、松尾英将、富澤大輔、足立壮一、多賀崇、小川誠司、林泰秀
  • Organizer: 第63回小児血液がん学会
• [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 (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