Role of GATA2 in bone marrow stromal cells

• Project/Area Number: 16K09819
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Okitsu Yoko 東北大学, 医学系研究科, 助教 (80451558)
• Project Period (FY): 2016-01-27 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: GATA-2 / 間葉系幹細胞 / 再生不良性貧血 / 造血微小環境

Outline of Final Research Achievements

The bone marrow (BM) microenvironment comprises multiple stem cell niches derived from BM mesenchymal stem cells (BM-MSCs). Previous in vitro analyses have suggested that transcription factor GATA2 plays an important role in adipocyte differentiation of BM-mesenchymal stem cells as well as in hematopoietic support, but the role of GATA2 in vivo remains unknown. We evaluated GATA2 effects in BM-MSC in vivo. We did not find any phenotypic changes when Gata2 was deleted with BM-MSC-related gene promoters, such as Nestin, Prx1, and Lepr, except for a significant decrease in the colony number of Gata2f/f/Prx1-Cre mice. Noticeably, there was a significant decrease in the percentage of the CMP fraction when Gata2 was deleted in all BM cells except for hematopoietic cells, after normal BM cells were transplanted into irradiated Gata2f/f/ER-Cre mice, with Gata2 subsequently knocked out by tamoxifen administration. In conclusion, GATA2 could affect the function of BM-MSCs in vivo.

Academic Significance and Societal Importance of the Research Achievements

本研究では，in vivoにおけるGata2の骨髄微小環境での機能を検討してきた．Gata2は造血前駆細胞における増殖や分化の制御のみではなく，BM-MSCにおいてもニッチとしての機能を制御し，HSCから骨髄球系共通前駆細胞およびリンパ球系共通前駆細胞への分化調節を担っている可能性があり，この機序としてはITGA11やITGB3，カテプシンGをはじめとした細胞接着因子や走化性因子が候補として考えられた．しかし，BM-MSCからHSCへのシグナル伝達経路に関しては検討が不十分であり，今後の課題として取り組んでいくべき点であると思われた．

Research Products

• [Journal Article] A case of myelodysplastic syndrome with t(10;18)(q26;q21) (2019)
  • Author(s): Ohba Yusuke、Yamada-Fujiwara Minami、Minagawa Tadanori、Watanabe Suguru、Okitsu Yoko、Izumi Yoshihiko、Kameoka Junichi、Takahashi Shinichiro
  • Journal Title: Journal of Laboratory Physicians Volume: 11 Issue: 04 Pages: 382-384
  • DOI: 10.4103/jlp.jlp_61_19
  • Peer Reviewed / Open Access
• [Journal Article] Long-term survival after cord blood transplantation for acute myeloid leukemia complicated with disseminated fusariosis (2019)
  • Author(s): Ichikawa S, Fukuhara N, Watanabe S, Okitsu Y, Onodera K, Onishi Y, Harigae H
  • Journal Title: J Infect Chemother Volume: 26 Issue: 2 Pages: 292-295
  • DOI: 10.1016/j.jiac.2019.08.022
  • Peer Reviewed
• [Journal Article] Establishment of a Screening System to Identify Novel GATA-2 Transcriptional Regulators (2018)
  • Author(s): Ohashi K, Fujiwara T, Onodera K, Saito Y, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Harigae H.
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 244 Issue: 1 Pages: 41-52
  • DOI: 10.1620/tjem.244.41
  • NAID: 130006315364
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Dynamics of absorption, metabolism, and excretion of 5-aminolevulinic acid in human intestinal Caco-2 cells. (2017)
  • Author(s): Saito K, Fujiwara T, Ota U, Hatta S, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Ishizuka M, Tanaka T, Harigae H
  • Journal Title: Biochemistry and Biophysics Reports Volume: 11 Pages: 105-111
  • DOI: 10.1016/j.bbrep.2017.07.006
  • Peer Reviewed / Open Access
• [Journal Article] Effects of in vivo deletion of GATA2 in bone marrow stromal cells (2017)
  • Author(s): Hasegawa S, Fujiwara T, Okitsu Y, Kato H, Sato Y, Fukuhara N, Onishi Y, Shimizu R, Yamamoto M, Harigae H.
  • Journal Title: Experimental Hematology Volume: 56 Pages: 31-45
  • DOI: 10.1016/j.exphem.2017.08.004
  • Peer Reviewed / Open Access
• [Journal Article] A novel heterozygous ALAS2 mutation in a female with macrocytic sideroblastic anemia resembling myelodysplastic syndrome with ring sideroblasts: a case report and literature review (2017)
  • Author(s): Fujiwara T, Fukuhara N, Ichikawa S, Kobayashi M, Okitsu Y, Onishi Y, Furuyama K, Harigae H
  • Journal Title: Annals of Hematology Volume: 96(11) Issue: 11 Pages: 1955-1957
  • DOI: 10.1007/s00277-017-3106-7
  • Peer Reviewed / Open Access
• [Journal Article] Forced FOG1 expression in erythroleukemia cells: Induction of erythroid genes and repression of myelo-lymphoid transcription factor PU.1. (2017)
  • Author(s): Fujiwara T, Sasaki K, Saito K, Hatta S, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Harigae H.
  • Journal Title: Biochem Biophys Res Commun Volume: 485 Issue: 2 Pages: 380-387
  • DOI: 10.1016/j.bbrc.2017.02.068
  • Peer Reviewed
• [Journal Article] Impact of TET2 deficiency on iron metabolism in erythroblasts. (2017)
  • Author(s): Inokura K, Fujiwara T, Saito K, Iino T, Hatta S, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Shimoda K, Harigae H
  • Journal Title: Exp Hematol. Volume: - Pages: 56-67
  • DOI: 10.1016/j.exphem.2017.01.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] An Lysophosphatidic Acid Receptors 1 and 3 Axis Governs Cellular Senescence of Mesenchymal Stromal Cells and Promotes Growth and Vascularization of Multiple Myeloma. (2017)
  • Author(s): Kanehira M, Fujiwara T, Nakajima S, Okitsu Y, Onishi Y, Fukuhara N, Ichinohasama R, Okada Y, Harigae H.
  • Journal Title: Stem Cells. Volume: 35 Issue: 3 Pages: 739-753
  • DOI: 10.1002/stem.2499
  • Peer Reviewed
• [Journal Article] Identification of a novel putative mitochondrial protein FAM210B associated with erythroid differentiation. (2016)
  • Author(s): Kondo A, Fujiwara T, Okitsu Y, Fukuhara N, Onishi Y, Nakamura Y, Sawada K, Harigae H.
  • Journal Title: Int J Hematol. Volume: 103 Issue: 4 Pages: 387-395
  • DOI: 10.1007/s12185-016-1968-4
  • Peer Reviewed
• [Journal Article] GATA2 regulates dendritic cell differentiation. (2016)
  • Author(s): Onodera K, Fujiwara T, Onishi Y, Itoh-Nakadai A, Okitsu Y, Fukuhara N, Ishizawa K, Shimizu R, Yamamoto M, Harigae H.
  • Journal Title: Blood Volume: 128 Issue: 4 Pages: 508-518
  • DOI: 10.1182/blood-2016-02-698118
  • Peer Reviewed / Open Access
• [Presentation] Establishment of a screening system to identify novel GATA-2 transcriptional regulators (2018)
  • Author(s): Ohashi K, Fujiwara T, Onodera K, Saito Y, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Harigae H
  • Organizer: 第80回日本血液学会総会
• [Presentation] Six cases of acquired hemophilia: Aingle center experience. (2017)
  • Author(s): Ichikawa S, Okitsu Y, Fukuhara N, Ono K, Himuro M, Hatta S, Kobayashi M, Onodera K, Kohata K, Yamamoto J, Onishi Y, Fujiwara M, Harigae H.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Generation of induced pluripotent stem cell-derived erythroblasts from a patient with X-linked sideroblastic anemia. (2016)
  • Author(s): Hatta S, Fujiwara T, Yamamoto T, Kamata M, Tamai Y, Nakamura Y, Kawamata S, Harigae H
  • Organizer: 第58回米国血液学会
  • Place of Presentation: サンディエゴ, アメリカ
  • Year and Date: 2016-12-02
  • Int'l Joint Research
• [Presentation] Identification of a novel putative mitochondrial protein FAM210B associated with erythroid differentiation. (2016)
  • Author(s): Kondo A, Fujiwara T, Okitsu Y, Fukuhara N, Onishi Y, Nakamura Y, Sawada K, Harigae H
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Impact of TET2 deficiency on iron metabolism in erythroblasts. (2016)
  • Author(s): Saito K, Inokura K, Fujiwara T, Hatta S, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Shimoda K, Harigae H
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Remarks] 東北大学血液・免疫病学分野
  • URL: http://www.rh.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学 血液免疫病学分野
  • URL: http://www.rh.med.tohoku.ac.jp/index.html