Clarifying clonal architecture diversity of leukemia dervied from myelodysplastic syndromes

• Project/Area Number: 20K17412
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Nippon Medical School
• Principal Investigator: Nagata Yasunobu 日本医科大学, 医学部, 講師 (90739575)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥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: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 骨髄異形成症候群 / 次世代シーケンサー / クローン進化 / クローン構造 / 白血病

Outline of Research at the Start

骨髄異形成症候群は造血クローンが増大し高率に白血病に移行する難治性の造血器腫瘍である。どのようなメカニズムでクローン構造が変化し白血病に進展してくのかは未だ明らかでない。申請者はがん細胞と正常細胞を明確に分画できる実験手法と遺伝子コピー数解析・次世代シークエンス技術を融合させ新たな統合的解析手法の実績があった。本研究では、MDS発症から白血病に至るまでの時系列サンプルの解析を行い、時間的・空間的なクローン進化の多様性を網羅的かつ正確に追尾し解析する。これによりMDSの分子基盤が解明され治療効果を予測する遺伝学的マーカーの探索が可能となり、有効かつ副作用の少ない新たな治療法の開発が期待される。

Outline of Final Research Achievements

The purpose of this study was to analyze samples over time from myelodysplastic syndrome to acute leukemia in order to elucidate the mechanism of tumorigenesis that promotes tumorigenesis and ultimately progresses to leukemia.
Targeted sequencing analysis was used to identify gene mutations with high sensitivity, and the clonal evolution could be accurately tracked by focusing on allele frequencies. Correlation analysis with clinical information, including prognosis and adverse events, revealed that the response to novel drugs such as BCL2 inhibitors can be stratified by genetic abnormalities such as TP53 and IDH1/2.
These results are of great importance in predicting treatment response using genetic abnormalities and helping to select the optimal treatment for individual patients.

Academic Significance and Societal Importance of the Research Achievements

遺伝子変異を持つ実際の患者に最も有効な治療法を選択する手法は定まっていないため、経時的試料を解析することで、腫瘍化を促進させ最終的に白血病に進展する腫瘍発症メカニズムを明らかにし、新たな治療戦略の構築に資することを目指していた。
本成果により、治療抵抗性に関わる遺伝子異常やその特徴が明らかとなり、実際の患者に適切な治療を選択するための新たな要因となった点で学術的意義が高い。
今後、前向きな臨床試験で本成果が検証され、治療成績の改善というエビデンスが期待される点で社会的意義が高いと考える。

Research Products

• [Journal Article] Epstein-Barr Virus-Related Hemophagocytic Lymphohistiocytosis with Central Nervous System Symptoms (2023)
  • Author(s): Sakaguchi Masahiro、Nagata Yasunobu、Terasaki Yasuhiro、Takeyoshi Atsushi、Yasuda Shunichi、Honma Shunsuke、Kinoshita Ryosuke、Marumo Atsushi、Asayama Toshio、Yui Shunsuke、Wakita Satoshi、Okamoto Muneo、Kajimoto Yusuke、Inokuchi Koichi、Yamaguchi Hiroki
  • Journal Title: Journal of Nippon Medical School Volume: 90 Issue: 1 Pages: 126-135
  • DOI: 10.1272/jnms.JNMS.2023_90-105
  • ISSN: 1345-4676, 1347-3409
  • Year and Date: 2023-02-25
  • Peer Reviewed / Open Access
• [Journal Article] Germ line <i>DDX41</i> mutations define a unique subtype of myeloid neoplasms (2023)
  • Author(s): Makishima H, Saiki R, Nannya Y, (17人省略), Kon A, (28人省略), Maciejewski JP, Ogawa S.
  • Journal Title: Blood Volume: 141 Issue: 5 Pages: 534-549
  • DOI: 10.1182/blood.2022018221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Amplified <i>EPOR</i>/<i>JAK2</i> Genes Define a Unique Subtype of Acute Erythroid Leukemia (2022)
  • Author(s): Takeda J, Kenichi Y, (9人省略), Kon A (12/41番目), (途中省略), Makishima H, Ogawa S
  • Journal Title: Blood Cancer Discovery Volume: 3 Issue: 5 Pages: 410-427
  • DOI: 10.1158/2643-3230.bcd-21-0192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Safety and efficacy of high‐dose cytarabine MEAM therapy and other treatments for auto‐peripheral blood stem cell transplantation: A retrospective comparative study (2022)
  • Author(s): Yui Shunsuke、Wakita Satoshi、Nagata Yasunobu、Omori Ikuko、Kinoshita Ryosuke、Takeyoshi Atsushi、Yasuda Shunichi、Honma Shunsuke、Nakayama Kazutaka、Hirakawa Tsuneaki、Arai Kunihito、Kitano Tomoaki、Okamoto Muneo、Inokuchi Koiti、Yamaguchi Hiroki
  • Journal Title: Asia-Pacific Journal of Clinical Oncology Volume: 19 Issue: 1 Pages: 136-148
  • DOI: 10.1111/ajco.13780
  • Peer Reviewed
• [Journal Article] A geno-clinical decision model for the diagnosis of myelodysplastic syndromes. (2021)
  • Author(s): Radakovich N, Meggendorfer M, Malcovati L, Hilton CB, Sekeres MA, Shreve J, Rouphail Y, Walter W, Hutter S, Galli A, Pozzi S, Elena C, Padron E, Savona MR, Gerds AT, Mukherjee S, Nagata Y, Komrokji RS, Jha BK, Haferlach C, Maciejewski JP, Haferlach T, Nazha A.
  • Journal Title: Blood Advances Volume: 5(21) Issue: 21 Pages: 4361-4369
  • DOI: 10.1182/bloodadvances.2021004755
  • Peer Reviewed / Open Access
• [Journal Article] Share Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia. (2021)
  • Author(s): Awada H, Durmaz A, Gurnari C, Kishtagari A, Meggendorfer M, Kerr CM, Kuzmanovic T, Durrani J, Shreve J, Nagata Y, Radivoyevitch T, Advani AS, Ravandi F, Carraway HE, Nazha A, Haferlach C, Saunthararajah Y, Scott J, Visconte V, Kantarjian H, Kadia T, Sekeres MA, Haferlach T, Maciejewski JP.
  • Journal Title: Blood Volume: 138(19) Issue: 19 Pages: 1885-1895
  • DOI: 10.1182/blood.2020010603
  • Peer Reviewed
• [Journal Article] Analysis of distinct SF3B1 hotspot mutations in relation to clinical phenotypes and response to therapy in myeloid neoplasia (2020)
  • Author(s): Adema Vera、Khouri Jack、Ni Ying、Rogers Heesun J.、Awada Hassan、Nagata Yasunobu、Kuzmanovic Teodora、Advani Anjali S.、Gerds Aaron T.、Mukherjee Sudipto、Nazha Aziz、Saunthararajah Yogen、Madanat Yazan、Patel Bhumika J.、Sol Francesc、Nawrocki Steffan T.、Maciejewski Jaroslaw P.、Visconte Valeria、Carraway Hetty E.
  • Journal Title: Leukemia & Lymphoma Volume: 62 Issue: 3 Pages: 735-738
  • DOI: 10.1080/10428194.2020.1839647
  • Peer Reviewed
• [Journal Article] Rare germline variant contributions to myeloid malignancy susceptibility (2020)
  • Author(s): Li Samuel T.、Wang Janet、Wei Ruipeng、Shi Ruqi、Adema Vera、Nagata Yasunobu、Kerr Cassandra M.、Kuzmanovic Teodora、Przychodzen Bartlomiej、Sole Francesc、Maciejewski Jaroslaw P.、LaFramboise Thomas
  • Journal Title: Leukemia Volume: 34 Issue: 6 Pages: 1675-1678
  • DOI: 10.1038/s41375-019-0701-8
  • Peer Reviewed
• [Journal Article] Machine learning demonstrates that somatic mutations imprint invariant morphologic features in myelodysplastic syndromes (2020)
  • Author(s): Nagata Yasunobu、Zhao Ran、Awada Hassan、Kerr Cassandra M.、Mirzaev Inom、Kongkiatkamon Sunisa、Nazha Aziz、Makishima Hideki、Radivoyevitch Tomas、Scott Jacob G.、Sekeres Mikkael A.、Hobbs Brian P.、Maciejewski Jaroslaw P.
  • Journal Title: Blood Volume: 136 Issue: 20 Pages: 2249-2262
  • DOI: 10.1182/blood.2020005488
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Clinical impact of IDH1/2 mutations in AML patients treated with Venetoclax (2022)
  • Author(s): Jiadan Sheng, Yasunobu Nagata, Masahiro Sakaguchi, Kunihito Arai, Junya Kuroda, Yuhei Nagao, Jiro Tadokoro, Hitoji Uchiyama, Shinya Kimura, Sayuri Motomura, Eriko Sato, Masao Ogata, Kenjiro Mitsuhashi, Jun Ando, Junya Kanda, Eri Kawata, Noriko Doki, Shinichiro Mori, Atsushi Satake, Hiroki Yamaguchi
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] The clinical and genetic features of Japanese de novo AML with IDH1/2 and SRSF2 mutations (2022)
  • Author(s): Mika Iwakiri, Yasunobu Nagata, Jiadan Sheng, Atsushi Marumo, Satoshi Wakita, Junya Kuroda, Jiro Tadokoro, Shinya Kimura, Sayuri Motomura, Eriko Sato, Junya Kanda, Eri Kawata, Nobuhiko Uoshima, Shinichi Kako, Yoshinobu Kanda, Katsuhiro Shono, Atsushi Satake, Hiroki Yamaguchi
  • Organizer: 第84回日本血液学会学術集会
• [Book] 血液内科 第85巻第1号 骨髄異形成症候群の個別化予後予測モデル (2022)
  • Author(s): 永田安伸
  • Total Pages: 6
  • Publisher: 科学評論社