Functional relationship between cell fate decision and epigenetic control of gene expression of the chromosome

• Project/Area Number: 26670465
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: KITAMURA TOSHIO 東京大学, 医科学研究所, 教授 (20282527)
• Co-Investigator(Kenkyū-buntansha): INABA Toshiya 広島大学, 原爆放射線医科学研究所, 教授 (60281292) ; MATSUI Hirotaka 熊本大学, 大学院生命科学研究部, 教授 (60379849)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エピジェネティクス / 細胞分化 / ヒストン修飾 / スプライシング / 好中球

Outline of Final Research Achievements

A human leukemic cell line HL60 differentiates to granulocytes and monocytes in response to retinoic acid and vitamin D3 treatment, respectively. In this project, we performed RNAseq analysis serially, and searched genes whose expression increases during the differentiation processes. In the results, we have identified several such genes. However, in contrast to our prediction, these genes do not localize in the neighborhood of chromosomes. Therefore, to investigate the roles of epigenetics in the differentiation of HL60 cells, we next knocked down an epigenetic factor ASXL1 involved in histone modification and analyzed the relationship between cell differentiation and histone modification. We have found that ASXL1 knockdown decreases trimethylation of histone H3K4 and H3K27 leading to inhibition of the differentiation of HL60 cells.

Research Products

• [Journal Article] UBASH3B/Sts-1-CBL axis regulates myeloid proliferation in human preleukemia induced by AML1^ETO. (2016)
  • Author(s): Goyama, S.
  • Journal Title: Leukemia Volume: 30 Issue: 3 Pages: 728-739
  • DOI: 10.1038/leu.2015.275
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Truncation mutants of ASXL1 observed in myeloid malignancies are expressed at detectable protein levels. (2016)
  • Author(s): Inoue D, Matsumoto M, Nagase R, Saika M, Fujino T, Nakayama KI, Kitamura T.
  • Journal Title: Exp Hematol. Volume: 44 Issue: 3 Pages: 172-176
  • DOI: 10.1016/j.exphem.2015.11.011
  • Peer Reviewed
• [Journal Article] Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD). (2016)
  • Author(s): Kitamura T, Watanabe-Okochi N, Enomoto Y, Nakahara F, Oki T, Komeno Y, Kato N, Doki N, Uchida T, Kagiyama Y, Togami K, Kawabata KC, Nishimura K, Hayashi Y, Nagase R, Saika M, Fukushima T, Asada S, Fujino T, Izawa Y, Horikawa S, Fukuyama T, Tanaka Y, Ono R, Goyama S, Nosaka T, Kitaura J, Inoue D
  • Journal Title: Journal of Biochemistry Volume: 159 Issue: 1 Pages: 17-25
  • DOI: 10.1093/jb/mvv114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The stability of epigenetic factor ASXL1 is regulated through ubiquitination and USP7-mediated deubiquitination. (2015)
  • Author(s): Inoue, D., Nishimura, K., Kozuka-Hata, H., Oyama, M. and Kitamura, T.
  • Journal Title: Leukemia Volume: in press Issue: 11 Pages: 2257-2260
  • DOI: 10.1038/leu.2015.90
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-C(m)) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-C(m). (2015)
  • Author(s): Togami K, Kitaura J, Uchida T, Inoue D, Nishimura K, Kawabata KC, Nagase R, Horikawa S, Izawa K, Fukuyama T, Nakahara F, Oki T, Harada Y, Harada H, Aburatani H, Kitamura T.
  • Journal Title: Exp Hematol. Volume: 43(4) Issue: 4 Pages: 300-308
  • DOI: 10.1016/j.exphem.2014.11.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS. (2015)
  • Author(s): Inoue D, Kitaura J, Matsui H, Hou HA, Chou WC, Nagamachi A, Kawabata KC, Togami K, Nagase R, Horikawa S, Saika M, Micol JB, Hayashi Y, Harada Y, Harada H, Inaba T, Tien HF, Abdel-Wahab O, Kitamura T.
  • Journal Title: Leukemia Volume: 29(4) Issue: 4 Pages: 847-57
  • DOI: 10.1038/leu.2014.301
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Thrombin receptor Par-1 enhances leukemia stem cell activity in MLL-fusion leukemia (2015)
  • Author(s): 合山進
  • Organizer: 第77回日本血液学会
  • Place of Presentation: ホテル金沢・石川県金沢市
  • Year and Date: 2015-10-18
• [Presentation] Identification of Runx1-direct targets important for definitive hematopoiesis (2015)
  • Author(s): 田中洋介
  • Organizer: 第77回日本血液学会
  • Place of Presentation: ホテル金沢・石川県金沢市
  • Year and Date: 2015-10-17
• [Presentation] Analysis of MDS mice model induced by ASXL1 and RUNX1 mutations (2015)
  • Author(s): 永瀬玲奈
  • Organizer: 第77回日本血液学会
  • Place of Presentation: ホテル金沢・石川県金沢市
  • Year and Date: 2015-10-17
• [Presentation] Molecular roles of ASXL1 mutations in inducing myelodysplastc syndromes (MDS) (2015)
  • Author(s): 北村俊雄
  • Organizer: 第７４回日本癌学会
  • Place of Presentation: 名古屋国際会議場・愛知県名古屋市
  • Year and Date: 2015-10-09
• [Presentation] Novel roles of ASXL1 in epigenetic regulation (2015)
  • Author(s): 井上大地
  • Organizer: THE ISEH 44th Annual Scientific Meeting
  • Place of Presentation: 国立京都国際会館・京都府京都市
  • Year and Date: 2015-09-18
  • Int'l Joint Research
• [Presentation] Identification of Runx1-direct targets important for definitive hematopoiesis (2015)
  • Author(s): 田中洋介
  • Organizer: THE ISEH 44th Annual Scientific Meeting
  • Place of Presentation: 国立京都国際会館・京都府京都市
  • Year and Date: 2015-09-18
  • Int'l Joint Research
• [Presentation] 造血器腫瘍発症の分子機構 (2015)
  • Author(s): 北村俊雄
  • Organizer: 第１６回 Pharmaco-Hematologyシンポジウム
  • Place of Presentation: 長井記念ホール・東京都渋谷区
  • Year and Date: 2015-06-13
  • Invited
• [Presentation] Molecular basis by which mutations of epigenetic factors induce MDS-like symptons. (2015)
  • Author(s): K. Kawabata, D. Inoue and T. Kitamura.
  • Organizer: 日米造血器腫瘍シンポジウム
  • Place of Presentation: ハワイ島・米国
  • Year and Date: 2015-03-16 – 2015-03-18
  • Invited
• [Presentation] 骨髄系造血器腫瘍発症の分子機構 (2014)
  • Author(s): 北村俊雄
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] C-terminal truncation type of RUNX1 mutants induce MDS/AML via gain-of-function mechanisms (2014)
  • Author(s): H.Harada, Y.Harada, D.Inoue, Y.Ding, G.Sashida, A.Iwama, H.Nakajima, J.Tanaka, N.Komatsu, T.Kitamura.
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Dominant negative EZH2 promotes myeloid tumorigenesis in mouse BMT model. (2014)
  • Author(s): K.Kawabata, D.Inoue, J.Kitaura, T.Kitamura.
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02