Developmental impact of MLL-AF4fusion gene on early hematopoieticstem cells

• Project/Area Number: 22591162
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Ehime University
• Principal Investigator: EGUCHI Mariko 愛媛大学, 大学院・医学系研究科, 准教授 (40420781)
• Co-Investigator(Kenkyū-buntansha): EGUCHI Minenari 愛媛大学, 医学部附属病院, 講師 (50420782) ; ISHII Eichi 愛媛大学, 大学院・医学系研究科, 教授 (20176126)
• Co-Investigator(Renkei-kenkyūsha): NAKAHATA Tatsutoshi 京都大学, iPS 細胞研究センター, 教授 (20110744)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 小児腫瘍学 / MLL / ES細胞 / 造血細胞分化 / 白血病

Research Abstract

To study the developmental impact of MLL-AF4 fusion gene on early hematopoietic development, mouse embryonic stem (ES) cells with constitutive expression of MLL-AF4 were established. When hematopoietic differentiation was examined by embryoid body (EB) formation, Tie2^+c-kit^+cells which contain early hematopoietic stem cells were significantly reduced in MLL-AF4 expressing Ebs compared to that of control Ebs.Expression array analysis indicated that MLL-AF4 works as positive regulator of gene expression up-regulating various genes. Several genes up-regulated by MLL-AF4 were known to have important roles in cell differentiation to mesenchymal lineage, whereas transcriptional regulator of hematopoietic lineage were down-regulated. These MLL-AF4 expressing pre-hematopoietic stem cells with mesenchymal nature, were unable to cause leukemia in vitroor in vivo, showing that some secondary event is necessary to cause leukemia. MLL-AF4, having the potential to influence early hematopoietic cell differentiation, may cause leukemic transformation whenaccompanied by some important additional genetic events.

Research Products

• [Journal Article] Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements (2013)
  • Author(s): M. Nishi, M. Eguchi-Ishimae, Z. Wu, W. Gao, H. Iwabuki, S. Kawakami, H. Tauchi, T. Inukai, K. Sugita, Y. Hamasaki, E. Ishii and M. Eguchi
  • Journal Title: Leukemia Volume: 27巻2号 Pages: 389-397
  • Peer Reviewed
• [Journal Article] 同種造血幹細胞移植後にドナー細胞由来の骨髄異形成症候群/急性骨髄性白血病を発症した小児白血病の検討 (2013)
  • Author(s): 徳田桐子、河上早苗、江口真理子、石前峰斉、本田美里、田内久道、石井榮一
  • Journal Title: 日本小児血液・がん学会雑誌 Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements (2013)
  • Author(s): Masanori Nishi
  • Journal Title: Leukemia Volume: 27 Issue: 2 Pages: 389-397
  • DOI: 10.1038/leu.2012.242
  • Peer Reviewed
• [Journal Article] 同種造血幹細胞移植後にドナー細胞由来の骨髄異形成症候群／急性骨髄性白血病を発症した小児白血病の検討 (2013)
  • Author(s): 徳田桐子
  • Journal Title: 日本小児血液・がん学会雑誌 Volume: 50 Pages: 43-49
  • Peer Reviewed
• [Journal Article] リンパ球機能異常と類縁疾患 原発性免疫不全症候群 Ataxia-telangiectasia (2013)
  • Author(s): 石前峰斉
  • Journal Title: 別冊日本臨床 新領域別症候群シリーズ 血液症候群（第2版) その他の血液疾患を含めて II Volume: 22 Pages: 288-292
• [Journal Article] Hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation in children: a nationwide survey in Japan (2012)
  • Author(s): T. Asano, K. Kogawa, A. Morimoto, Y. Ishida, N. Suzuki, S. Ohga, K. Kudo, S. Ohta, H. Wakiguchi, K. Tabuchi, S. Kato and E. Ishii
  • Journal Title: Pediatr Blood Cancer Volume: 59巻1号 Pages: 110-114
  • Peer Reviewed
• [Journal Article] Clinical features and outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of flow cytometric assay and genetic analysis (2012)
  • Author(s): H. Kanegane, X. Yang, M. Zhao, K. Yamato, M. Inoue, K. Hamamoto, C. Kobayashi, A. Hosono, Y. Ito, Y. Nakazawa, K. Terui, K. Kogawa, E. Ishii, R. Sumazaki and T. Miyawaki
  • Journal Title: Pediatr Allergy Immunol Volume: 23巻5号 Pages: 488-493
  • Peer Reviewed
• [Journal Article] Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to display effective antileukemia reactivity (2012)
  • Author(s): K. Nagai, T. Ochi, H. Fujiwara, J. An, T. Shirakata, J. Mineno, K. Kuzushima, H. Shiku, J. J. Melenhorst, E. Gostick, D. A. Price, E. Ishii and M. Yasukawa
  • Journal Title: Blood Volume: 119巻2号 Pages: 368-376
  • Peer Reviewed
• [Journal Article] CBL mutations in infant acute lymphoblastic leukaemia (2012)
  • Author(s): N. Shiba, M. J. Park, T. Taki, J. Takita, M. Hiwatari, T. Kanazawa, M. Sotomatsu, E.Ishii, H. Arakawa, S. Ogawa and Y. Hayashi
  • Journal Title: Br J Haematol Volume: 156巻5号 Pages: 672-674
  • Peer Reviewed
• [Journal Article] Novel dominant-negative mutant of GATA3 in HDR syndrome (2011)
  • Author(s): M. Ohta, M. Eguchi-Ishimae, M. Ohshima, H. Iwabuki, K. Takemoto, K. Murao, T. Chisaka, E. Yamamoto, T. Higaki, K. Isoyama, M. Eguchi and E. Ishii
  • Journal Title: J Mol Med (Berl) Volume: 89巻1号 Pages: 43-50
  • Peer Reviewed
• [Journal Article] Rapid diagnosis of FHL3 by flow cytometric detection of intraplatelet Munc13-4 protein. (2011)
  • Author(s): Y. Murata, T. Yasumi, R. Shirakawa, K. Izawa, H. Sakai, J. Abe, N. Tanaka, T. Kawai, K. Oshima, M. Saito, R. Nishikomori, O. Ohara, E. Ishii, T. Nakahata, H. Horiuchi and T. Heike
  • Journal Title: Blood Volume: 118巻5号 Pages: 1225-1230
  • Peer Reviewed
• [Journal Article] Successful treatment of very large congenital infantile fibrosarcoma (2011)
  • Author(s): A. Hamidah, M. Reena, A. R. Halim, S. Ibrahim, M. Eguchi, A. L. Zarina, K. N. Norazlin, R. Jamal and H. Kanegane
  • Journal Title: Pediatr Int Volume: 53巻5号 Pages: 768-770
  • Peer Reviewed
• [Journal Article] Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry (2011)
  • Author(s): M. Zhao, H. Kanegane, C. Kobayashi, Y. Nakazawa, E. Ishii, M. Kasai, K. Terui, Y. Gocho, K. Imai, J. Kiyasu, S. Nonoyama and T. Miyawaki
  • Journal Title: Cytometry B Clin Cytom Volume: 80巻1号 Pages: 8-13
  • Peer Reviewed
• [Journal Article] 小児白血病とTEL遺伝子異常 (2011)
  • Author(s): 江口真理子、石前峰斉
  • Journal Title: 臨床血液 Volume: 52巻 Pages: 686-694
  • NAID: 10029615153
• [Journal Article] 小児白血病とTEL遺伝子異常 (2011)
  • Author(s): 江口真理子
  • Journal Title: 臨床血液 Volume: 52 Pages: 686-694
  • NAID: 10029615153
  • Peer Reviewed
• [Journal Article] Successful treatment of very large congenital infantile fibrosarcoma (2011)
  • Author(s): Hamidah, A
  • Journal Title: Pediatrics International Volume: 53 Pages: 768-770
  • Peer Reviewed
• [Journal Article] 小児ALL,乳児白血病とDNAメチル化異常 (2011)
  • Author(s): 石前峰斉, 他
  • Journal Title: Annual Review血液2011 Pages: 137-146
• [Journal Article] Novel dominant-negative mutant of GATA3 in HDR syndrome (2011)
  • Author(s): Ohta, M, et al.
  • Journal Title: J Mol Med Volume: 89 Pages: 43-50
  • Peer Reviewed
• [Journal Article] Nationwide survey of single-system single site Langerhans cell histiocytosis in Japan (2010)
  • Author(s): A. Morimoto, Y. Ishida, N. Suzuki, S. Ohga, Y. Shioda, Y. Okimoto, K. Kudo and E. Ishii
  • Journal Title: Pediatr Blood Cancer Volume: 54巻1号 Pages: 98-102
  • Peer Reviewed
• [Journal Article] Subtypes of familial hemophagocytic lymphohistiocytosis in Japan based on genetic and functional analyses of cytotoxic T lymphocytes (2010)
  • Author(s): K. Nagai, K. Yamamoto, H. Fujiwara, J. An, T. Ochi, K. Suemori, T. Yasumi, H. Tauchi, K. Koh, M. Sato, A. Morimoto, T. Heike, E. Ishii and M. Yasukawa
  • Journal Title: PLoS One Volume: 5巻11号
  • Peer Reviewed
• [Journal Article] ETV6-ARNT fusion in a patient with childhood T lymphoblastic leukemia (2010)
  • Author(s): K. Otsubo, , H. Kanegane, M. Eguchi, M. Eguchi-Ishimae, K. Tamura, K. Nomura, A. Abe, E. Ishii and T. Miyawaki
  • Journal Title: Cancer Genet Cytogenet Volume: 202巻1号 Pages: 22-26
  • Peer Reviewed
• [Journal Article] ETV6-ARNT fusion in a patient with childhood T lymphoblastic leukemia (2010)
  • Author(s): Otsubo, K, et al.
  • Journal Title: Cancer Genet Cytogenet Volume: 202 Pages: 22-26
  • Peer Reviewed
• [Presentation] 播種性病変を認めたDesmoplastic infantile astrocytoma の1例 (2012)
  • Author(s): 徳田桐子、河上早苗、手束真理、田内久道、石前峰斉、江口真理子、石井榮一
  • Organizer: 第54回日本小児血液・がん学会
  • Place of Presentation: 横浜
  • Year and Date: 2012-11-30
• [Presentation] Munc13-4ミスセンス変異による学童期発症FHL3型の症例 (2012)
  • Author(s): 中野直子、越智史博、永井功造、八角高裕、河上早苗、石前峰斉、江口真理子、田内久道、石井榮一
  • Organizer: 第54回日本小児血液・がん学会
  • Place of Presentation: 横浜
  • Year and Date: 2012-11-30
• [Presentation] Developmental impact of MLL-AF4 fusion gene on early hematopoietic stem cells (2012)
  • Author(s): 石前峰斉、江口真理子、石井榮一
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] X-linked chronic granulomatous disease in a young female due to skewed inactivation of the X-chromosome (2012)
  • Author(s): 八木千裕、石前峰斉、河上早苗、田内久道、徳田桐子、江口真理子、石井榮一、岡田 賢、小林 正夫
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] MicroRNA let-7b is a target of leukemogenic MLL fusion protein and in activated by DNA hyper-methylation (2011)
  • Author(s): 石前(江口)峰斉
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] G13D KRAS mutation was found in Flk1-positive cells in a case of JMML (2011)
  • Author(s): 徳田桐子
  • Organizer: 第73回日本血液学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-14
• [Presentation] 下大静脈から右心室まで進展し緊急に心臓内腫瘍摘出術を行った副腎原発神経芽腫の1例 (2011)
  • Author(s): 本田美里、河上早苗、田内久道、石前峰斉、江口真理子、石井榮一、亀岡一裕、長島光樹
  • Organizer: 第53回日本小児血液学会・がん学会
  • Place of Presentation: 前橋
• [Presentation] MicroRNA let-7b is a target of leukemogenic MLL fusion protein and inactivated by DNA hyper-methylation (2011)
  • Author(s): 石前峰斉、江口真理子、西 真範、田内久道、河上早苗、杉田完爾、石井榮一
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 名古屋
• [Presentation] KRAS mutation was found in FLK1-positive cells in a case of JMML (2011)
  • Author(s): 徳田桐子、江口真理子、石前峰斉、河上早苗、本田美里、田内久道、石井榮一
  • Organizer: 第72回日本血液学会
  • Place of Presentation: 名古屋
• [Presentation] 2回目の同種造血幹細胞移植後にドナー由来の二次性MDSを発症した再発乳児ALLの1例. (2011)
  • Author(s): 河上早苗、徳田桐子、田内久道、本田美里、石前峰斉、江口真理子、石井榮一
  • Organizer: 第73回日本血液学会
  • Place of Presentation: 名古屋
• [Presentation] 韓国の小児急性リンパ性白血病におけるIKZF1、ARID5BおよびCEBPE遺伝子変異の意義 (2011)
  • Author(s): 韓東均、石前峰斉、江口真理子、石井榮一
  • Organizer: 第114回日本小児科学会
  • Place of Presentation: 東京
• [Presentation] 正着不全のため3回の同種造血幹細胞移植を行い骨髄内臍帯血移植を併用した急性リンパ性白血病の女児例 (2011)
  • Author(s): 河上早苗、田内久道、石前峰斉、江口真理子、石井榮一
  • Organizer: 第33回日本造血幹細胞移植学会
  • Place of Presentation: 愛媛
• [Presentation] 腹腔内desmoplastic small round cell tumorの男児 (2010)
  • Author(s): 河上早苗
  • Organizer: 第52回日本小児血液学会総会・第26回日本小児がん学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2010-12-17
• [Presentation] Implication of Genetic Variations of Ikzf1, ARIDB5, and CEBPE Genes In the Risk of Childhood Acute Lymphoblastic Leukemia in Korea (2010)
  • Author(s): Dong Kyun Han
  • Organizer: 第52回米国血液学会総会
  • Place of Presentation: Orland, Florida, USA
  • Year and Date: 2010-12-06
• [Presentation] 小児白血病とTEL遺伝子異常 (2010)
  • Author(s): 江口真理子
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-26
• [Presentation] A TEL-ARNT fusion in a boy with T lymphoblastic leukemia (2010)
  • Author(s): 大坪慶輔
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Concordant expression of TEL-AML1 fusion and c-Myc amplification in a patient with B-precursor ALL (2010)
  • Author(s): 河上早苗
  • Organizer: 第72回日本血液学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] 腹腔内desmoplastic small round cell tumorの男児 (2010)
  • Author(s): 河上早苗、田内久道、渡部竜助、宮脇零士、石前峰斉、江口真理子、石井榮一、堀内淳、亀岡一裕
  • Organizer: 第52回日本小児血液学会、第26回日本小児がん学会
  • Place of Presentation: 大阪
• [Presentation] Implication of genetic variations of Ikzf1, ARIDB5, and CEBPE genes in the risk of childhood acute lymphoblastic leukemia in Korea. (2010)
  • Author(s): Han DK, Kim HN, Shin M-H, Eguchi-Ishimae M, Eguchi M, Ishii E, Baek HJ, Park SJ, Kim HJ, Hwang TJ, Kook H
  • Organizer: 52nd Annual Meeting of American Society of Hematology
  • Place of Presentation: Orland, USA
• [Presentation] 急性リンパ性白血病の再々発時にTEL-AML1の増幅とc-mycの増幅を認めた1男児 (2010)
  • Author(s): 河上早苗、田内久道、石前峰斉、江口真理子、石井榮一
  • Organizer: 第72回日本血液学会
  • Place of Presentation: 横浜
• [Presentation] 小児白血病とTEL遺伝子異常 (2010)
  • Author(s): 江口真理子、石前峰斉、石井榮一
  • Organizer: 第72回日本血液学会
  • Place of Presentation: 横浜
• [Presentation] 呼吸管理が必要であった血友病A早産児における補充療法の適応について (2010)
  • Author(s): 河上早苗、田内久道、千阪俊行、太田雅明、石前峰斉、江口真理子、石井榮一
  • Organizer: 第20回日本産婦人科・新生児血液学会
  • Place of Presentation: 静岡
• [Presentation] HDR 症候群に認められたGATA3 遺伝子の新規変異とその機能解析 (2010)
  • Author(s): 大嶋麻友美、江口真理子、石前峰斉、太田雅明、村尾紀久子、竹本幸司、石井榮一
  • Organizer: 第113回日本小児科学会
  • Place of Presentation: 盛岡
• [Presentation] Developmental impact of MLL-AF4 fusion gene on early hematopoietic stem cells
  • Author(s): 石前峰斉
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] X-linked chronic granulomatous disease in a young female due to skewed inactivation of the X-chromosome
  • Author(s): 八木千裕
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
• [Presentation] 播種性病変を認めたDesmoplastic infantile astrocytomaの1例
  • Author(s): 徳田桐子
  • Organizer: 第54回日本小児血液・がん学会
  • Place of Presentation: 横浜
• [Presentation] Munc13-4ミスセンス変異による学童期発症FHL3型の症例
  • Author(s): 中野直子
  • Organizer: 第54回日本小児血液・がん学会
  • Place of Presentation: 横浜
• [Book] リンパ球機能異常と類縁疾患 原発性免疫不全症候群Ataxia-telangiectasia、日本臨床別冊 血液症候群(第2版)II -その他の血液疾患を含めて (2013)
  • Author(s): 石前峰斉、江口真理子
• [Book] 小児ALL、乳児白血病とDNAメチル化異常、Annual Review 血液 (2011)
  • Author(s): 石前峰斉、江口真理子
  • Publisher: 中外医学社