Multistep molecular mechanisms for acute megakaryoblastic leukemia in Down syndrome
Project/Area Number |
18H04039
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Medium-sized Section 52:General internal medicine and related fields
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Research Institution | Hirosaki University |
Principal Investigator |
Ito Etsuro 弘前大学, 医学研究科, 特任教授 (20168339)
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Co-Investigator(Kenkyū-buntansha) |
照井 君典 弘前大学, 医学研究科, 教授 (00333740)
工藤 耕 弘前大学, 医学部附属病院, 助教 (20455728)
土岐 力 弘前大学, 医学研究科, 講師 (50195731)
金崎 里香 弘前大学, 医学研究科, 助教 (60722882)
|
Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥44,070,000 (Direct Cost: ¥33,900,000、Indirect Cost: ¥10,170,000)
Fiscal Year 2020: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2019: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
Fiscal Year 2018: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
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Keywords | ダウン症候群 / TAM / 急性巨核芽球性白血病 / MYC/E2F経路 / GATA1 / 付加的遺伝子異常 / 急性巨核芽性白血病 |
Outline of Final Research Achievements |
About 10% of neonates with Down syndrome (DS: trisomy 21) develop TAM, which is characterized by rapid proliferation of abnormal blast cells. It frequently progresses to acute megakaryoblastic leukemia (DS-AMKL) after spontaneous regression, whose mechanism has not fully been elucidated. We identified novel mutational targets including the IRX1, ZBTB7A and NFIA genes, inactivation of which is implicated in an upregulated MYC/E2F pathway. We also found frequent partial tandem duplications (PTD) affecting the RUNX1 gene, which induced leukemia in a knock-in mouse model. Highly specific to DS-AMKL, these lesions highlight the mechanism that is unique to DS-related myeloid leukemogenesis.
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Academic Significance and Societal Importance of the Research Achievements |
ダウン症(DS)は、多段階の白血病発症機構を解明する上で貴重な疾患である。本研究では、複数の異なる遺伝子の不活化変異により、DS-AMKL細胞でMYC/E2F経路の活性化が起こることを初めて明らかにした。共通に障害されるMYC経路などを標的にした革新的な新規治療法の開発が期待できる。さらに、21番染色体上に存在するRUNX1遺伝子のPTDをDS-AMKLで高頻度に見出した。RUNX1-PTDノックインマウスを用いて、この構造異常が実際に白血病の多段階発症に重要な役割を果たすことを明らかにした。本研究成果は、全ての白血病の発症機構の解明と治療法の開発に役立つことが期待される。
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Report
(4 results)
Research Products
(33 results)
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[Journal Article] Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome2021
Author(s)
Yamato G, Deguchi T, Terui K, Toki T, Watanabe T, Imaizumi T, Hama A, Iwamoto S, Hasegawa D, Ueda T, Yokosuka T, Tanaka S, Yanagisawa R, Koh K, Saito AM, Horibe K, Hayashi Y, Adachi S, Mizutani S, Taga T, Ito E, Watanabe K, Muramatsu H.
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Journal Title
Leukemia.
Volume: 35
Issue: 5
Pages: 1480-1484
DOI
Related Report
Peer Reviewed
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[Journal Article] Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency.2021
Author(s)
Anfeng Mu, Asuka Hira, Akira Niwa, Mitsujiro Osawa, Kenichi Yoshida, Minako Mori, Yusuke Okamoto, Kazuko Inoue, Keita Kondo, Masato T. Kanemaki, Tomonari Matsuda, Etsuro Ito, Seiji Kojima, Tatsutoshi Nakahata, Seishi Ogawa, Keigo Tanaka, Keitaro Matsuo, Megumu K. Saito, Minoru Takata.
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Journal Title
Blood
Volume: 137
Issue: 15
Pages: 2021-2032
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Down syndrome-related transient abnormal myelopoiesis is attributed to a specific erythro-megakaryocytic subpopulation with GATA1 mutation.2021
Author(s)
Nishinaka-Arai Y, Niwa A, Matsuo S, Kazuki Y, Yakura Y, Hiroma T, Toki T, Sakuma T, Yamamoto T, Ito E, Oshimura M, Nakahata T, Saito MK.
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Journal Title
Haematologica
Volume: 106(2)
Issue: 2
Pages: 635-640
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.2020
Author(s)
Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, Anmae M, Yasuda J, Tadaka S, Kinoshita K, Osumi T, Noguchi Y, Adachi S, Kobayashi R, Kawabata H, Imai K, Morio T, Tamura K, Takaori-Kondo A, Yamamoto M, Miyano S, Kojima S, Ito E, Ogawa S, Matsuo K, Yabe H, Yabe M, Takata M.
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Journal Title
Haematologica
Volume: 105
Issue: 4
Pages: 1166-116
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing.2019
Author(s)
Terui K, Toki T, Taga T, Iwamoto S, Miyamura T, Hasegawa D, Moritake H, Hama A, Nakashima K, Kanezaki R, Kudo K, Saito AM, Horibe K, Adachi S, Tomizawa D, Ito E.
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Journal Title
Genes Chromosomes Cancer.
Volume: -
Issue: 3
Pages: 160-167
DOI
Related Report
Peer Reviewed
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[Journal Article] A Rapid Cytologic Double Staining of Epstein-Barr Virus-encoded Small RNA and Cell Surface Markers for Diagnosis of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis2019
Author(s)
Takahashi N, Kudo K, Tanaka M, Kumagai N, Sato T, Kamio T, Sasaki S, Terui K, Kurose A, Yanagisawa R, Nakazawa Y, Ito E.
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Journal Title
J Pediatr Hematol Oncol.
Volume: -
Issue: 8
Pages: 1-1
DOI
Related Report
Peer Reviewed
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[Journal Article] Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.2019
Author(s)
Watanabe A, Inukai T, Kagami K, Abe M, Takagi M, Fukushima T, Fukushima H, Nanmoku T, Terui K, Ito T, Toki T, Ito E, Fujimura J, Goto H, Endo M, Look T, Kamps M, Minegishi M, Takita J, Inaba T, Takahashi H, Ohara A, Harama D, Shinohara T, Somazu S, Oshiro H, Akahane K, Goi K, Sugita K.
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Journal Title
Cancer Med.
Volume: 7
Issue: 11
Pages: 5274-5288
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells.2019
Author(s)
Kohara H, Utsugisawa T, Sakamoto C, Hirose L, Ogawa Y, Ogura H, Sugawara A, Liao J, Aoki T, Iwasaki T, Asai T, Doisaki S, Okuno Y, Muramatsu H, Abe T, Kurita R, Miyamoto S, Sakuma T, Shiba M, Yamamoto T, Ohga S, Yoshida K, Ogawa S, Ito E, Kojima S, Kanno H, Tani K.
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Journal Title
Related Report
Peer Reviewed
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[Journal Article] Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.2019
Author(s)
Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, Anmae M, Yasuda J, Tadaka S, Kinoshita K, Osumi T, Noguchi Y, Adachi S, Kobayashi R, Kawabata H, Imai K, Morio T, Tamura K, Takaori-Kondo A, Yamamoto M, Miyano S, Kojima S, Ito E, Ogawa S, Matsuo K, Yabe H, Yabe M, Takata M.
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Journal Title
Haematologica.
Volume: -
Issue: 10
Pages: 1962-1973
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia.2019
Author(s)
Yabe M, Koike T, Ohtsubo K, Imai E, Morimoto T, Takakura H, Koh K, Yoshida K, Ogawa S, Ito E, Okuno Y, Muramatsu H, Kojima S, Matsuo K, Mori M, Hira A, Takata M, Yabe H.
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Journal Title
Ann Hematol.
Volume: 98
Issue: 2
Pages: 271-280
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Two siblings with familial neuroblastoma with distinct clinical phenotypes harboring an ALK germline mutation.2018
Author(s)
Kudo K, Ueno H, Sato T, Kubo K, Kanezaki R, Kobayashi A, Kamio T, Sasaki S, Terui K, Kurose A, Yoshida K, Shiozawa Y, Toki T, Ogawa S, Ito E.
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Journal Title
Genes Chromosomes Cancer.
Volume: 57
Issue: 12
Pages: 665-669
DOI
Related Report
Peer Reviewed
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[Journal Article] De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome2018
Author(s)
Toki Tsutomu、Yoshida Kenichi、Wang RuNan、Okuno Yusuke、Kataoka Keisuke、Shiraishi Yuichi、Ohga Shouichi、Kuramitsu Madoka、Hamaguchi Isao、Ohara Akira、Kanno Hitoshi、Miyano Satoru、Kojima Seiji、Ishiguro Akira、Sugita Kanji、Kenmochi Naoya、Takahashi Satoru、Eto Koji、Ogawa Seishi、Ito Etsuro
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Journal Title
The American Journal of Human Genetics
Volume: 103
Issue: 3
Pages: 440-447
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms2018
Author(s)
Tsujimoto S, Osumi T, Uchiyama M, Shirai R, Moriyama T, Nishii R, Yamada Y, Kudo K, Sekiguchi M, Arakawa Y, Yoshida M, Uchiyama T, Terui K, Ito S, Koh K, Takita J, Ito E, Tomizawa D, Manabe A, Kiyokawa N, Yang JJ, Kato M.
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Journal Title
Leukemia
Volume: 32
Issue: 12
Pages: 2710-2714
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] BRAFV600E-POSITIVE PRECURSORS AS MOLECULAR MARKERS OF BONE MARROW INVOLVEMENT IN PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS.2019
Author(s)
Ko Kudo, Rika Kanezaki, Masaru Imamura, Chihaya Imai, Masahiro Irie, Yoji Sasahara, Kumiko Ando, Harumi Kakuda, Takehiko Doi, Hiroshi Kawaguchi, Kazuko Kudo, Hirokazu Kanegane, Tsutomu Toki, and Etsuro Ito.
Organizer
35th Annual Meeting of the Histiocyte Society
Related Report
Int'l Joint Research
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[Presentation] Integrated genetic and epigenetic analysis elucidated expression and methylation profiles of acute lymphoblastic leukemia in Down syndrome2018
Author(s)
Yasuo Kubota, Kumiko Uryu, Tatsuya Ito, Tomoko Kawai, Masafumi Seki, Tomoya Isobe, Tsutomu Toki, Kenichi Yoshida, Keisuke Kataoka, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Akira Oka, Yasuhide Hayashi, Seishi Ogawa, Kiminori Terui, Atsushi Sato, Kenichiro Hata, Etsuro Ito, Junko Takita.
Organizer
The 23th Congress of European Hematology Association
Related Report
Int'l Joint Research
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[Presentation] Modelling the progression of a preleukemic stage to overt leukemia in children with Down syndrome2018
Author(s)
M. Labuhn, K. Perkins, E Papaemmanuil, S Matzk, C Scheer, Kenichi Yoshida, A Schwarzer, J Taub, J Crispino, MJ Weiss, E Ito, Seishi Ogawa, ML Yaspo, PJ Campbell, D Heckl, JH Klusmann, P Vyas.
Organizer
The 60th American Society of Hematology
Related Report
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[Presentation] Clinical and genetic characteristics of patients with Shwachman-Diamond syndrome in Japan2018
Author(s)
Kenichiro Watanabe, Hirokazu Kanegane, Takayuki Hamabata, Kagehiro Kozuki, Katsutsugu Umeda, Asahito Hama, Yusuke Okuno, Hideki Muramatsu, Yoshiyuki Takahashi, Daisuke Hasegawa, Atsushi Manabe, Akira Ohara, Masafumi Ito, Seiji Kojima, Etsuro Ito
Organizer
The 60th American Society of Hematology
Related Report
Int'l Joint Research
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