Understanding of the onset and recurrence pattern of intractable acute lymphocytic leukemia based on clone analysis
Project/Area Number |
20K08723
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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 54010:Hematology and medical oncology-related
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Research Institution | National Hospital Organization Nagoya Medical Center |
Principal Investigator |
Sanada Masashi 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)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 急性リンパ性白血病 / 微小残存病変 / クローン構造 / 乳児白血病 / KMT2A転座 / 遺伝子再構成 / クローン変化 / 再発 |
Outline of Research at the Start |
クローン進化に基づく多様性の獲得は多くのがんに共通する現象であり、クローン構造や進展過程の解明は、がんの病態理解において重要である。急性リンパ性白血病(ALL)においては、免疫グロブリンおよびT細胞受容体遺伝子の再構成を用いた腫瘍クローンの定量評価に基づく微小残存病変(MRD)による層別化治療が行われている。本研究では、難治性であるMLL転座陽性ALLを主たる対象として、転座のゲノム上の切断点評価と合わせることで、発症、治療経過中の残存病変、再発時における、より正確なクローン構造を明らかとする。難治性ALLのMRD評価法ならびに治療開発の基盤となる再発・難治に関わる病態の解明を目指す。
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Outline of Final Research Achievements |
In this study, we performed target-capture sequencing to identify clonal IGH-VDJ rearrangements and genomic breakpoints of MLL (KMT2A) rearrangements. We quantified these clone sizes by droplet-digital PCR to elucidate detailed clonal structures in ALL cases with MLL rearrangement. In the KMT2A::AFF1 or KMT2A::MLLT1 cases, multiple IGH-DJ rearrangements were identified, and most cases were composed of various minor clones in cells with KMT2A rearrangement. On the other hand, ALL cases with MLL rearrangement to other genes have a limited number of rearrangements and were composed of simple monoclonal structures. Oligoclonal IGH rearrangements were also identified in infant ALL cases without KMT2A rearrangements, but most of the rearrangements were complete V(D)J type. KMT2A::AFF1 and MLLT1 cases were often difficult to evaluate minimal residual disease using IGH rearrangements, and MRD evaluation using genomic KMT2A breakpoints was considered useful alternative.
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Academic Significance and Societal Importance of the Research Achievements |
乳児ALLがoligoclonalな再構成を有していることは既に知られていたが、本解析により単に再構成の数では表せないクローン構造を正確に示すことができた。KMT2A転座例において転座切断点を用いたMRD評価の有用性は次期臨床試験において前向きに検証予定であるが、転座相手遺伝子によって、その重要性は異なることが明らかとなった。クローン構造の理解に基づく正確なMRD評価は、再発リスク評価による治療成績の改善や新規治療開発の治療判定に寄与するとともに、不必要な造血幹細胞移植やCART療法を回避することの臨床的、医療経済的な意義は非常に大きいと考える。
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Report
(4 results)
Research Products
(38 results)
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[Journal Article] Clinical characteristics and outcomes of B-cell precursor ALL with MEF2D rearrangements: a retrospective study by the Ponte di Legno Childhood ALL Working Group.2023
Author(s)
Ohki K, Butler ER, Kiyokawa N, Hirabayashi S, Bergmann AK, Mテカricke A, Boer JM, Cavテゥ H, Cazzaniga G, Yeoh AEJ, Sanada M, Imamura T, Inaba H, Mullighan CG, Loh ML, Norテゥn-Nystrテカm U, Shih LY, Zaliova M, Pui CH, Haas OA, Harrison CJ, Moorman AV, Manabe A.
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Journal Title
Leukemia.
Volume: 37
Issue: 1
Pages: 212-216
DOI
Related Report
Peer Reviewed
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[Journal Article] Unraveling unique features of plasma cell clones in POEMS syndrome with single-cell analysis.2022
Author(s)
Isshiki Y, Oshima M, Mimura N, Kayamori K, Miyamoto-Nagai Y, Seki M, Nakajima-Takagi Y, Kanamori T, Iwamoto E, Muto T, Tsukamoto S, Takeda Y, Ohwada C, Misawa S, Ikeda JI, Sanada M, Kuwabara S, Suzuki Y, Sakaida E, Nakaseko C, Iwama A.
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Journal Title
JCI Insight
Volume: 7
Issue: 20
Pages: 1-13
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma.2021
Author(s)
Kunou S, Shimada K, Takai M, Sakamoto A, Aoki T, Hikita T, Kagaya Y, Iwamoto E, Sanada M, Shimada S, Hayakawa F, Oneyama C, Kiyoi H.
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Journal Title
Oncogene
Volume: 40
Issue: 23
Pages: 3989-4003
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Clinical utility of target capture‐based panel sequencing in hematological malignancies: A multicenter feasibility study2020
Author(s)
Yasuda T, Sanada M, Nishijima D, Kanamori T, Iijima Y, Hattori H, Saito A, Miyoshi H, Ishikawa Y, Asou N, Usuki K, Hirabayashi S, Kato M, Abe M.
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Journal Title
Cancer Science
Volume: 111
Issue: 9
Pages: 3367-3378
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Br J Haematol.
Volume: -
Issue: 5
Pages: 755-763
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Intensification of Early-Phase Therapy to Diminish the Prognostic Effect of Myeloid Antigen Expression in Infants with KMT2A-Rearranged Acute Lymphoblastic Leukemia: A Report from the JPLSG MLL-10 Trial.2021
Author(s)
Yuki Arakawa, Takashi Ishihara, Takako Miyamura, Takao Deguchi, Masashi Sanada, Toshinori Hori, Tomomi Yamada, MD, Yuki Aoki, Sae Ishimaru, Takayuki Takachi, Mio Yano, Shinya Sasaki, Akiko M Saito, Atsushi Manabe, Keizo Horibe, Toshihiko Imamura, Daisuke Tomizawa.
Organizer
63rd American Society of Hematology Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] ターゲットキャプチャシーケンスによる乳児白血病のクロナリティ分析2021
Author(s)
Tomomi Yamada, Yuka Iijima, Takako Miyamura, Toshihiko Imamura, Toshinori Hori, Akiko Saito, Atsushi Manabe, Keizo Horibe, Daisuke Tomizawa, Masashi Sanada
Organizer
第63回日本小児血液がん学会
Related Report
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