Identification of GATA2 function in dendritic cell differentiation for elucidating the pathological mechanism of MonoMAC syndrome

• Project/Area Number: 26860716
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Onishi Yasushi 東北大学, 大学病院, 講師 (10509574)
• Research Collaborator: Onodera Koichi 東北大学, 大学院医学系研究科・血液免疫病学分野 (80792291)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: GATA2 / MonoMAC症候群 / 樹状細胞 / 転写因子 / MonoMＡＣ症候群 / 間葉系幹細胞 / 造血幹細胞

Outline of Final Research Achievements

Mutations in GATA2 are associated with the monocytopenia and mycobacterial infection (MonoMAC) syndrome. In this syndrome, monocyte, B-cell, NK-cell, and dendritic cell (DC) populations are diminished or undetectable. DCs are central regulators for immune response. We investigated the role of GATA2 in DC differentiation and function by Gata2 conditional knockout mice. It was found that GATA2 was required for the in vitro generation of DCs from common myeloid-restricted progenitors and common DC precursors. But common lymphoid-restricted progenitors or granulocyte-macrophage progenitors were not affected for the DC differentiation by GATA2-knockout. Moreover, expression profiling showed GATA2 could suppress T-cell-related genes, including Gata3 and Tcf7 in myeloid progenitors. These findings suggest GATA2 has an important role in cell-fate specification toward the myeloid vs. T-cell lineage by regulating lineage-specific transcription factors in progenitors.

Research Products

• [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
• [Journal Article] High-Throughput siRNA Screening to Reveal GATA-2 Upstream Transcriptional Mechanisms in Hematopoietic Cells. (2015)
  • Author(s): Saito Y, Fujiwara T, Ohashi K, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Harigae H.
  • Journal Title: PLoS One Volume: 10 Issue: 9 Pages: e0137079-e0137079
  • DOI: 10.1371/journal.pone.0137079
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of acquired mutations by whole-genome sequencing in GATA-2 deficiency evolving into myelodysplasia and acute leukemia. (2014)
  • Author(s): Fujiwara, T., Fukuhara, N., Funayama, R., Nariai, N., Kamata, M., Nagashima, T., Kojima, K., Onishi, Y., Sasahara, Y., Ishizawa, K., Nagasaki, M., Nakayama, K. & Harigae, H
  • Journal Title: Ann Hematol Volume: 93 Issue: 9 Pages: 1515-1522
  • DOI: 10.1007/s00277-014-2090-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GATA2 regulates differentiation of bone marrow-derived mesenchymal stem cells. (2014)
  • Author(s): Kamata M, Okitsu Y, Fujiwara T, Kanehira M, Nakajima S, Takahashi T, Inoue A, Fukuhara N, Onishi Y, Ishizawa K, Shimizu R, Yamamoto M, Harigae H.
  • Journal Title: Haematologica Volume: 99 Issue: 11 Pages: 1686-1696
  • DOI: 10.3324/haematol.2014.105692
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Outcome of cord blood transplantation in adult patients with chronic active Epstein-Barr Virys infection (2017)
  • Author(s): Yasushi Onishi, Masahiro Kobayashi, Shunsuke Hatta, Satoshi Ichikawa, Noriko Fukuhara, Tohru Fujiwara, Minami Fujiwara, Hideo Harigae
  • Organizer: European Society for Blood and Marrow Transplantation (EBMT2017)
  • Place of Presentation: Palais des Congres－Marseille Chanot, マルセイユ、フランス
  • Year and Date: 2017-03-26
  • Int'l Joint Research
• [Presentation] GATA-2 Regulates Dendritic Cell Differentiation (2015)
  • Author(s): Koichi Onodera, Tohru Fujiwara, Yasushi Onishi, Ari Itoh-Nakadai, Yoko Okitsu, Noriko Fukuhara, Kenichi Ishizawa, Ritsuko Shimizu, masayuki Yamamoto,Hideo Harigae
  • Organizer: American Society of Hematology 57th Annual Meeting&Exposition
  • Place of Presentation: アメリカ、オーランド
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Adult MDS cases diagnosed as MonoMAC syndrome (2014)
  • Author(s): Nakagawa R, Fukuhara N, Okitsu Y, Takahashi T, Katsuoka Y, Kobayashi M, Onishi Y, Fujiwara T, Sasahara Y, Ishizawa K, Harigae H.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場 大阪市
  • Year and Date: 2014-10-31 – 2014-11-02
• [Remarks] 東北大学 血液免疫病学分野
  • URL: http://www.rh.med.tohoku.ac.jp/index.html