The molecular pathogenenesis of pediatric acute lymphoblastic leukemia through the understanding of clonal artitectures

• Project/Area Number: 17K10136
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: National Hospital Organization Nagoya Medical Center
• Principal Investigator: Masashi Sanada 独立行政法人国立病院機構(名古屋医療センター臨床研究センター), その他部局等, 高度診断研究部長 (20529044)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 急性リンパ性白血病 / クローン / 遺伝子再構成 / クローン変化 / 再発 / クローン評価 / ゲノム

Outline of Final Research Achievements

For the purpose of identifying of Ig/TCR rearrangements in acute lymphoblastic leukemia (ALL), a comprehensive analysis of rearrangements using target-capture sequencing was performed, and in addition to the rearrangements used for the measurement of minimal residual disease, an extremely large number of rearrangements were detected. A time-course study of relapsed B-ALL cases suggests that the time to relapse, clonal diversity at the time of initial diagnosis, and depth of remission contributed to clonal changes. Understanding the clonal structure was considered important for understanding the pathogenesis of ALL and monitoring after treatment.

Academic Significance and Societal Importance of the Research Achievements

ALL診療において、腫瘍細胞特異的なIg/TCR再構成に基づく、微小残存病変の定量評価は、治療反応性を直接的に反映し、治療最適化に必須の検査となっている。PCR-MRDにおいて、腫瘍細胞特異的な再構成の同定の過程は非常に煩雑であったが、今回開発した検出系は効率的であり、有用性が高い。クローン構造の理解は、白血病の病態理解ならびに治療後のモニタリングのみならず、ALL以外のリンパ系腫瘍用においても有用であり、形質細胞性腫瘍のゲノム解析にも応用可能であった。

Research Products

• [Int'l Joint Research] CLIP, Charles University(チェコ)
• [Int'l Joint Research] Yong Loo Lin School of Medicine/National University of Singapore(シンガポール)
• [Journal Article] Genomic analysis of multiple myeloma using targeted capture sequencing in the Japanese cohort. (2020)
  • Author(s): Kanamori T, Sanada M, Ri M, Ueno H, Nishijima D, Yasuda T, Tachita T, Narita T, Kusumoto S, Inagaki A, Ishihara R, Murakami Y, Kobayashi N, Shiozawa Y, Yoshida K, Nakagawa MM, Nannya Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Horibe K, Handa H, Ogawa S, Iida S.
  • Journal Title: Br J Haematol. Volume: - Issue: 5 Pages: 755-763
  • DOI: 10.1111/bjh.16720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DNA methylation-based classification reveals difference between pediatric T-cell acute lymphoblastic leukemia and normal thymocytes (2019)
  • Author(s): Kimura Shunsuke、Ogawa Seishi., et al.
  • Journal Title: Leukemia Volume: 34 Issue: 4 Pages: 1163-1168
  • DOI: 10.1038/s41375-019-0626-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia (2019)
  • 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
  • Journal Title: Blood Adv Volume: 3 Issue: 20 Pages: 3157-3169
  • DOI: 10.1182/bloodadvances.2019000404
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Precision medicine for acute myeloid leukemia based on genomic profiling (2019)
  • Author(s): Sanada M
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 7 Pages: 847-853
  • DOI: 10.11406/rinketsu.60.847
  • NAID: 130007687994
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling (2019)
  • Author(s): Watatani Yosaku,Ogawa Seishi., et al.
  • Journal Title: Leukemia Volume: 33 Issue: 12 Pages: 2867-2883
  • DOI: 10.1038/s41375-019-0473-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent structural variations involving programmed death ligands in Epstein-Barr virus-associated lymphomas (2019)
  • Author(s): Kataoka Keisuke, Miyoshi Hiroaki, Sakata Seiji, Dobashi Akito, Couronne Lucile, Kogure Yasunori, Sato Yasuharu, Nishida Kenji, Gion Yuka, Shiraishi Yuichi, Tanaka Hiroko, et al
  • Journal Title: Leukemia Volume: Epub ahead of print Issue: 7 Pages: 1687-1699
  • DOI: 10.1038/s41375-019-0380-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and transcriptional landscape of plasma cells in POEMS syndrome (2019)
  • Author(s): Nagao Y, Mimura N, Takeda J, Yoshida K, Shiozawa Y, Oshima M, Aoyama K, Nishijima D, Isshiki Y, Kayamori K, Kawajiri-Manako C, Oshima-Hasegawa N, Tsukamoto S, Mitsukawa S, Takeda Y, Ohwada C, Takeuchi M, Iseki T, Misawa S, Miyano S, Ohara O, Yokote K, Sakaida E, Kuwabara S, Sanada M, Iwama A, Ogawa S, Nakaseko C.
  • Journal Title: Leukemia Volume: － Issue: 7 Pages: 1723-1735
  • DOI: 10.1038/s41375-018-0348-x
  • Peer Reviewed / Open Access
• [Journal Article] Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma (2019)
  • Author(s): Polprasert C, Takeuchi Y, Kakiuchi N, Yoshida K, Assanasen T, Sitthi W, Bunworasate U, Pirunsarn A, Wudhikarn K, Lawasut P, Uaprasert N, Kongkiatkamon S, Moonla C, Sanada M, Akita N, Takeda J, Fujii Y, Suzuki H, Nannya Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Rojnuckarin P, Ogawa S, Makishima H
  • Journal Title: Blood Advances Volume: 3 Issue: 4 Pages: 588-595
  • DOI: 10.1182/bloodadvances.2018028340
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. (2017)
  • Author(s): Seki M, Kimura S, Isobe T, Yoshida K, (13 authors), Masuda K, Kawamoto H, Ohki K, Kato M, Arakawa Y, Koh K, Hanada R, Moritake H, Akiyama M, Kobayashi R, Deguchi T, Hashii Y, Imamura T, Sato A, Kiyokawa N, Oka A, Hayashi Y, Takagi M, Manabe A, Ohara A, Horibe K, Sanada M, Iwama A, Mano H, Miyano S, Ogawa S, Takita J
  • Journal Title: Nature Genetics Volume: 49 Issue: 8 Pages: 1274-1281
  • DOI: 10.1038/ng.3900
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies (2017)
  • Author(s): Tanaka Tomoyuki、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Tara Shiro、Oshima Motohiko、Saraya Atsunori、Koide Shuhei、Si Sha、Manabe Ichiro、Sanada Masashi、Nakayama Manabu、Masuko Masayoshi、Sone Hirohito、Koseki Haruhiko、Iwama Atsushi
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2901-2913
  • DOI: 10.1084/jem.20170167
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxic adaptation of leukemic cells infiltrating the CNS affords a therapeutic strategy targeting VEGFA (2017)
  • Author(s): Kato Itaru、Nishinaka Yoko、Nakamura Masahiro、et al.
  • Journal Title: Blood Volume: 129 Issue: 23 Pages: 3126-3129
  • DOI: 10.1182/blood-2016-06-721712
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Target Capture Sequencing Method for Screening MRD Markers in Infant Leukemia. (2019)
  • Author(s): Masashi Sanada, Tomomi Yamada, Dai Nishijima, Yuka Iijima-Yamashita, Toshinori Hori, Keizo Horibe.
  • Organizer: ESH (1st International Conference-Acute Lymphoblastic Leukaemia)
  • Int'l Joint Research
• [Presentation] Comprehensive genetic analysis of multiple myeloma in Japan. (2019)
  • Author(s): Kanamori T, Sanada M, Ri M, Ueno H, Nishijima D, Yasuda T, Aoki S, Asano A, Tachita T, Kinoshita S, Narita T, Ito A, Kusumoto S, Masuda Y, Kobayashi N, Shiozawa Y, Nakagawa M, Nannya Y, Shiraishi Y, Chiba K, Tanaka H, Komatsu H, Miyano S, Handa H, Ogawa S, Iida S.
  • Organizer: 24th Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] 小児白血病のクリニカルシーケンスの展望 (2019)
  • Author(s): 真田 昌
  • Organizer: 第78回日本癌学会学術総会
  • Invited
• [Presentation] Clonality analysis of patients with infant leukemia by target-capture sequence. (2019)
  • Author(s): Masashi Sanada
  • Organizer: 8th ESLHO Educational meeting, 28th EuroMRD meeting
  • Int'l Joint Research
• [Presentation] Targeted-Capture Sequencing Is a Useful Method for MRD Markers Screening in KMT2A (MLL) Rearranged Leukemia (2019)
  • Author(s): Masashi Sanada, Tomomi Yamada, Yuka Iijima-Yamashita, Dai Nishijima, Takashi Kanamori, Daisuke Tomizawa, Toshinori Hori, Keizo Horibe
  • Organizer: 61st ASH Annual Meeting
  • Int'l Joint Research
• [Presentation] 小児白血病におけるゲノム医療の必要性 (2019)
  • Author(s): 真田 昌
  • Organizer: 第61回日本小児血液・がん学会
  • Invited
• [Presentation] Role of Blood Testing (2019)
  • Author(s): Masashi Sanada
  • Organizer: 3rd Annual Asian Myeloma Net Work Summit 2019
  • Int'l Joint Research / Invited
• [Presentation] Multicentre standardization of minimal residual disease detection and quantitation using the euroclonality-NGS assay. (2019)
  • Author(s): Svaton M, Fronkova E, Reigl T, Caye A, Bie M, Genuardi E, Jelinkova H, Lim E, Nishijima D, Pal K, Salemi D, Sarasquete M, Songia S, Tosi M, Villarese P, Wakeman S, Cave H, Cazzaniga G, Frrero S, Sanz RG, Hancock J, Macintyre E, Plevova K, Sanada M, et al.
  • Organizer: 24th Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] landscape of driver mutations and their clinical impacts in pediatric patients with B-progenitor acute lymphoblastic leukemia (2018)
  • Author(s): Hiroo Ueno, Kenichi Yoshida, Yasuhito Nannya, Yuka Iijima, Yusuke Shiozawa, Yuishi Shiraishi, Tomomi Ishida, Toshihiko Imamura, Satoru Miyano, Seishi Ogawa, Keizo Horibe, Masashi Sanada
  • Organizer: 29th Annual Meeting of the International BFM Study Group
  • Int'l Joint Research
• [Presentation] 成人B細胞性急性リンパ性白血病のゲノム学的・臨床的な特徴 (2018)
  • Author(s): 安田貴彦, 西島大, 小島進也, 河津正人, 上野敏秀, 都築忍, 清井仁, 松村到, 宮崎泰司, 堀部敬三, 間野博行, 直江知樹, 真田昌, 早川文彦
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] キャプチャー・シーケンス法を用いたIg/TCR遺伝子再構成クローンの効率的スクリーニングプロセス (2018)
  • Author(s): 西島大, 赤井畑美津子, 飯島友加, 山田朋美, 堀壽成, 白石友一, 田中洋子, 宮野悟, 堀部敬三, 真田昌
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 新規診断多発性骨髄腫における網羅的ゲノム解析 (2018)
  • Author(s): 金森貴之, 真田昌, 李政樹, 上野浩生, 西島大, 安田貴彦, 青木奨, 吉田嵩, 木下史緒理, 成田朋, 伊藤旭, 楠本茂, 増田裕太, 小林宣彦, 塩澤裕介, 吉田健一, 中川正宏, 南谷泰仁, 白石友一, 千葉健一, 田中洋子, 小松弘和, 宮野悟, 半田寛, 小川誠司, 飯田 真介
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 小児急性リンパ性白血病MRD測定不能例でのNGSによる新たなMRD測定マーカーの同定 (2018)
  • Author(s): 赤井畑美津子, 山田朋美, 山田美穂, 飯島友加, 西島大, 毛利真由, 石田智美, 麩山美華, 岡田佳奈子, 堀壽成, 真田昌, 堀部敬三
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 小児T細胞性急性リンパ性白血病におけるNOTCH1シグナル活性化変異の種類と臨床的特徴の解析 (2018)
  • Author(s): 木村俊介, 関正史, 吉田健一, 上野浩生, 塩澤裕介, 磯部知弥, 大木健太郎, 加藤元博, 康勝好, 小林良二, 出口隆生, 橋井佳子, 今村俊彦, 佐藤篤, 清河信敬, 真部淳, 堀部敬三, 小原明, 真田昌, 小林正夫, 岡明, 林泰秀, 宮野悟, 小川誠司, 滝田順子
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] High-throughput clonality analysis based on Ig/TCR gene rearrangements in acute lymphoblastic leukemia with capture sequencing (2018)
  • Author(s): Nishijima D, Akaihata M, Iijima-Yamashita Y, Yamada T, Shiraishi Y, Tanaka H, Hori T, Miyano S, Horibe K, Sanada M
  • Organizer: 7th ESLHO Symposium
  • Int'l Joint Research
• [Presentation] Capture Sequencing Is a Useful Method for Comprehensive Clonality Analysis Based on Ig/TCR Gene Rearrangements in Acute Lymphoblastic Leukemia. (2018)
  • Author(s): Dai Nishijima, Mitsuko Akaihata, Yuka Iijima-Yamashita, Tomomi Yamada, Yuichi Shiraishi, Hiroko Tanaka, Toshinori Hori, Satoru Miyano, Keizo Horibe and Masashi Sanada
  • Organizer: ASH2018
  • Int'l Joint Research
• [Presentation] Genomic and Clinical Characterization of Adult Ph-Negative B-Cell Acute Lymphoblastic Leukemia. (2018)
  • Author(s): Takahiko Yasuda, Dai Nishijima, Shinya Kojima, Masahito Kawazu, Toshihide Ueno, Shinobu Tsuzuki, Hitoshi Kiyoi, Itaru Matsumura, Yasushi Miyazaki, Keizo Horibe, Hiroyuki Mano, Tomoki Naoe, Masashi Sanada and Fumihiko Hayakawa
  • Organizer: ASH2018
  • Int'l Joint Research
• [Presentation] The Prognostic Value of TP53 Mutations Depends on Clinical Backgrounds in Pediatric Patients with Acute Lymphoblastic Leukemia (2018)
  • Author(s): Hiroo Ueno, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Yuka Iijima-Yamashita, Nobutaka Kiyokawa, Yoshiyuki Kosaka, Koji Kato, Takeshi Inukai, Junko Takita, Toshihiko Imamura, Satoru Miyano, Atsushi Manabe, Keizo Horibe Seishi Ogawa and Masashi Sanada
  • Organizer: ASH2018
  • Int'l Joint Research
• [Presentation] Distribution and Clinical Features of NOTCH1 Signaling Activating Alterations in Pediatric T-Cell Acute Lymphoblastic Leukemia (T-ALL) (2018)
  • Author(s): Shunsuke Kimura, Masafumi Seki, Kenichi Yoshida, Hiroo Ueno, Yasuhito Nannya, Kentaro Ohki, Motohiro Kato, Katsuyoshi Koh, Atsushi Sato, Nobutaka Kiyokawa, Atsushi Manabe, Keizo Horibe, Akira Ohara, Masashi Sanada, Mitsuteru Hiwatari, Masao Kobayashi, Akira Oka, Satoru Miyano, Seishi Ogawa and Junko Takita
  • Organizer: ASH2018
  • Int'l Joint Research
• [Presentation] Caputure sequencing approach to identify clonality of Ig/TCR gene rearrangement (2017)
  • Author(s): Dai Nishijima, Yuka Iijima-Yamashita, Shun Fujiwara, Yuichi Shiraishi, Hiroko Tanaka, Satoru Miyano, Tomomi Ishida, Mika Fuyama, Keizo Horibe, Masashi Sanada
  • Organizer: 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Quantitative detection of MRD targeting leukemia-specific single nucleotide variant (2017)
  • Author(s): Tomoo Osumi, Yuka Iijima-Yamashita, Shin-ichi Tsujimoto, Toru Uchiyama, Daisuke Tomizawa, Nobutaka Kiyokawa, Masashi Sanada, Motohiro Kato
  • Organizer: 79th Annual Meeting of the Japanese Society of Hematology
• [Presentation] Biomarker researches in acute leukemia for precision medicine (2017)
  • Author(s): Masashi Sanada
  • Organizer: 76th Annual Meeting of Japanese Cancer Association
  • Invited
• [Book] 血液疾患最新の治療2020-2022 (2019)
  • Author(s): 真田 昌
  • Total Pages: 300
  • Publisher: 南江堂
  • ISBN: 9784524249787
• [Book] EBM血液疾患の治療2019-2020 (2018)
  • Author(s): 金倉譲、木崎昌弘、鈴木律朗、神田善伸、北中明、大島孝一、牧島秀樹、吉里哲一、山崎宏人、後藤明彦、町田真一郎、新谷直樹、原田浩徳、鈴木隆浩、前田嘉信、川口辰哉、上野志貴子、小原直、眞田昌、宮本敏浩 他
  • Total Pages: 567
  • Publisher: 中外医学社
  • ISBN: 9784498225145