Epigenomic analysis in refractory AML
Project/Area Number |
19K08350
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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Research Institution | Yokohama City University |
Principal Investigator |
SHIBA Norio 横浜市立大学, 附属病院, 講師 (50600615)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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Keywords | 急性骨髄性白血病 / DNAメチル化 / ATAC-seq / micro RNA / Chipシーケンス / microRNAシーケンス / 遺伝子解析 / ATACシーケンス |
Outline of Research at the Start |
小児急性骨髄性白血病(AML)は小児がんの中でも予後不良な疾患の1つである。これまでの網羅的な遺伝子解析の結果、予後不良な遺伝子再構成であるNUP98-NSD1症例においてPRDM16 (MEL1) 遺伝子が高発現していることを同定し、PRDM16高発現症例ではPRDM16遺伝子全長に渡ってポリコーム遺伝子群との結合部位が高度にメチル化されており、interactionが阻害されている可能性を見出した。ポリコーム遺伝子群はHOX遺伝子群に作用し、幹細胞制御にかかわる重要な遺伝子群であり、これらの関係を明らかにし、創薬につながる分子標的の同定を試みたいと考えている。
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Outline of Final Research Achievements |
CHIP-seq was performed using a sample with acute myeloid leukemia harboring NUP98-NSD1 with high expression of PRDM16. As a result, some novel candidate genes were identified, in addition to known cancer-related genes such as SKI and RUNX1. ATAC-seq found that the promoter region of PRDM16 is open in the AML samples showing PRDM16 high expression. Intriguingly, same region showed low DNA methylation pattern, although gene body of PRDM16 gene itself was highly methylated resulting in inhibiting binding with Polycomb complex. These alteration contributes to the refractory AML. Furthermore, microRNA sequences were performed on 48 pediatric AMLs with carrying various genetic backgrounds. They classified them into four clusters based on expression patterns, some of which correlated with existing genetic abnormalities.
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Academic Significance and Societal Importance of the Research Achievements |
難治AML症例より同定された遺伝子異常の機能的な意義を解明することで、AMLの発症原因を解明し、創薬開発に繋げていくことで難治AML患者を救命することが可能となる。層別化については、これまでの解析にて概ね完了している。しかしながら、まだ約10%の患者においては、driverとなる遺伝子異常を見いだすことが出来ていない(これらの症例の多くは複雑な染色体の構造異常を認め、予後不良である)。よって、より高精度の治療層別化フローチャートを作成し、すべての小児AML症例の再発リスク、予後予測に基づいた適切な治療強度を選択できるようにするため、これらの10%の症例の発病原因を探索することに注力する。
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Report
(4 results)
Research Products
(39 results)
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[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.
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Journal Title
Blood advances
Volume: in press
Issue: 11
Pages: 3207-3219
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
British Journal of Haematology
Volume: 194(2)
Issue: 2
Pages: 414-422
DOI
Related Report
Peer Reviewed
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[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.
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Journal Title
Haematologica
Volume: -
Issue: 3
Pages: 583-592
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Predisposition to prolonged neutropenia after chemotherapy for paediatric acute myeloid leukaemia is associated with better prognosis in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML‐05 study.2020
Author(s)
Aoki T, Takahashi H, Tanaka S, Shiba N, Hasegawa D, Iwamoto S, Terui K, Moritake H, Nakayama H, Shimada A, Koh K, Goto H, Kosaka Y, Saito AM, Horibe K, Kinoshita A, Tawa A, Taga T, Adachi S, Tomizawa D.
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Journal Title
British Journal of Haematology
Volume: 193
Issue: 1
Pages: 176-180
DOI
Related Report
Peer Reviewed
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[Journal Article] The outcomes of relapsed acute myeloid leukemia in children: Results from the Japanese Pediatric Leukemia/Lymphoma Study Group AML‐05R study.2020
Author(s)
Moritake H, Tanaka S, Miyamura T, Nakayama H, Shiba N, Shimada A, Terui K, Yuza Y, Koh K, Goto H, Kakuda H, Saito A, Hasegawa D, Iwamoto S, Taga T, Adachi S, Tomizawa D.
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Journal Title
Pediatric Blood & Cancer
Volume: 68
Issue: 1
DOI
Related Report
Peer Reviewed
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[Journal Article] Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup.2020
Author(s)
Hara Y, Shiba N, Yamato G, Ohki K, Tabuchi K, Sotomatsu M, Tomizawa D, Kinoshita A, Arakawa H, Saito AM, Kiyokawa N, Tawa A, Horibe K, Taga T, Adachi S, Taki T, Hayashi Y
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Journal Title
Br J Haematol
Volume: 188
Issue: 4
Pages: 528-539
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] A 2‐year‐old patient with a diffuse intrinsic pontine glioma and radiation‐induced moyamoya syndrome.2020
Author(s)
Iizuka A, Shiba N, Shimosato Y, Yoshitomi M, Nakamura T, Miyatake S, Takano Y, Sasaki K, Takeuchi M, Nurata H, Yamamoto N, Ito S.
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Journal Title
Pediatric Blood & Cancer
Volume: 67
Issue: 10
DOI
Related Report
Peer Reviewed
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[Journal Article] Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia2019
Author(s)
Shiba N, Yoshida K, Hara Y, Yamato G, Shiraishi Y, Matsuo H, Okuno Y, Chiba K, Tanaka H, Kaburagi T, Takeuchi M, Ohki K, Sanada M, Okubo J, Tomizawa D, Taki T, Shimada A, Sotomatsu M, Horibe K, Taga T, Adachi S, Tawa A, Miyano S, Ogawa S, Hayashi Y
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Journal Title
Blood Adv
Volume: 3
Issue: 20
Pages: 3157-3169
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Br J Haematol.
Volume: 19
Issue: 2
Pages: 284-288
DOI
Related Report
Peer Reviewed
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[Presentation] Clonal Evolution Pattern and Prognostic Significance of Clonal Architecture in KMT2A-Rearranged Acute Myeloid Leukemia.2021
Author(s)
Matsuo H, Yoshida K, Nannya Y, Ito Y, Saito S, Koga Y, Moritake H, Terui K, Kawaguchi K, Okamoto Y, Nakayama H, Kanno M, Hino M, Akane Y, Inoue A, Shimada A, Goto H, Ueno H, Takita J, Yamato G, Shiba N, Hayashi Y, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Taga T, Tawa A, Ogawa S and Adachi S
Organizer
The 63rd American Society of Hematology Annual Meeting and Exposition(virtual)
Related Report
Int'l Joint Research
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[Presentation] Cytokine Analysis in 154 Patients with Transient Abnormal Myelopoiesis: Jccg JPLSG TAM-10 Clinical Study.2021
Author(s)
Yamato G, MD, Park MJ, Shimada A, Shiba N, Yamada Y, Terui K, Ito E, MD, Muramatsu H, Watanabe K, and Hayashi Y.
Organizer
The 63rd American Society of Hematology Annual Meeting and Exposition(virtual)
Related Report
Int'l Joint Research
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[Presentation] The genetic landscape of pediatric acute promyelocytic leukemia - the JCCG study, JPLSG AML-P05 -(小児急性骨髄性白血病に対するカスタムパネルを用いた網羅的遺伝子解析 - the JCCG study, JPLSG AML-P05 -2020
Author(s)
Yamato G, Ueno H, Takahashi H, Shiba N, Ohki K, Yuza Y, Tomizawa D, Adachi S, Ogawa S, Hayashi Y
Organizer
第62回日本小児血液・がん学会学術集会,福島( Web)
Related Report
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[Presentation] Etoposide, Cytarabine and Mitoxantrone- or Fludarabine, Cytarabine and Granulocyte Colony-Stimulating Factor-Based Intensive Reinduction Chemotherapy Is Recommended for Children with Relapsed Acute Myeloid Leukemia: The Results from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05R Study.2020
Author(s)
Moritake H, Tanaka S, Miyamura T, Nakayama H, Shiba N, Shimada A, Terui K, Yuza Y, Koh K, Goto H, Kakuda H, Saito A M, Hasegawa D, Iwamoto S, Taga T, Adachi S, Tomizawa D
Organizer
The 62nd ASH Annual Meeting and Exposition (virtual)
Related Report
Int'l Joint Research
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[Presentation] Comprehensive Genetic Analysis Revealed Myeloid/Natural Killer (NK) Cell Precursor Acute Leukemia As a Novel Distinctive Leukemia Entity.2020
Author(s)
Nishimura A, Yokoyama K, Yamagishi C, Imamura T, Naruto T, Morio T, Tanaka Y, Kanai A, Matsui H, Higuchi N, Shiba N, Miki M, Kimura F, Nakayama H, Nakazawa Y, Taga T, Taki T, Adachi S, Manabe A, Koh K, Ishida Y, Tojo A, Takagi M. et.al.
Organizer
The 62nd ASH Annual Meeting and Exposition (virtual)
Related Report
Int'l Joint Research
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[Presentation] The Detection of Minor Clones with Somatic KIT D8 16V Mutations Using Droplet Digital PCR in Pediatric De Novo AML: AML-05 Trial from the Japanese Pediatric Leukemia/ Lymphoma Study Group.2019
Author(s)
Sasaki K, Uchiyama Y, Ikeda J, Yoshitomi M, Shimosato-Wada Y, Tokumasu M, Matsuo H, Yoshida K, Oki K, Yamato G, Hara Y, Kinoshita A, Tomizawa D, Taga T, Adachi S, Tawa A, Horibe K, Matsumoto N, Ito S, Hayashi Y, Shiba N
Organizer
61st American Society of Hematology Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] Recurrent Gene Mutations in Peadiatric Patients with AML By Targeted Sequencing -the Jccg Study, JPLSG AML-05-.2019
Author(s)
Kaburagi T, Yamato G, Shiba N, Yoshida K, Hara Y, 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
Organizer
61st American Society of Hematology Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] Clinical Features of Pediatric Acute Myeloid Leukemia with TP53 and CDKN2A/2B copy Number Alterations.2019
Author(s)
Hara Y, Taki T, Yamato G, Yoshida K, Shiozawa Y, Shiba N, Kaburagi T, Shiraishi Y, Ohki K, Kawamura M, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Toki T, Kiyokawa N, Tomizawa D, Tago T, Ito E, Horibe K, Miyano S, Ogawa S, Adachi S, Hayashi Y
Organizer
61st American Society of Hematology Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] Significant Feature of DNA Methylation at Bivalent Promotor and Repressed Polycomb Regions in Padiatric AML-the Jccg Study, JPLSG AML-05-.2019
Author(s)
Yamato G, Kawai T, Shiba N, Hara Y, Ohki K, Kaburagi T, Yoshida K, Shiraishi Y, Miyano S, Kiyokawa N, Tomizawa D, Shimada A, Sotomatsu M, Arakawa H, Adachi S, Tago T, Horibe K, Ogawa S, Hata K, Hayashi Y
Organizer
61st American Society of Hematology Annual Meeting
Related Report
Int'l Joint Research
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[Presentation] Recurrent gene mutations in pediatric AML by targeted sequencing using a 343-gene custom panel.2019
Author(s)
Kaburagi T, Yamato G, Shiba N, Yoshida K, Hara Y, Shiraishi Y, Ohki K, Sotomatsu M, Arakawa H, Matsuo H, Shimada A, Taki T, Kiyokawa N, Tomizawa D, Horibe K, Miyano S, Adachi S, Taga T, Ogawa S, Hayashi Y
Organizer
81st Annual Meeting of the Japanese Society of Hematology
Related Report
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[Presentation] Comprehensive methylation analysis in pediatric AML patients -the JCCG, JPLSG AML-05 study-.2019
Author(s)
Yamato G, Kawai T, Shiba N, Hara Y, Ohki K,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
Organizer
81st Annual Meeting of the Japanese Society of Hematology
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