GATA2-mediated regulation of immune cell differentiation involved in immunodeficiency

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16074
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Tohoku University
• Principal Investigator: Hasegawa Atsushi 東北大学, 医学系研究科, 助教 (80747460)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: GATA2

Outline of Final Research Achievements

To elucidate the roles of GATA2, an indispensable transcription factor in hematopoiesis, for regulation of immune cell differentiation and the pathogenesis of GATA2-related diseases, we analyzed mouse model expressing GATA2R398W mutant found in disease patients and characterized molecular function of this mutant. This mouse line exhibited decrease of peripheral immune cells, containing B-cell, NK-cell, dendritic-cell and monocyte, and abnormal differentiation of B-cell in bone marrow. DNA binding ability and trans activation activity of GATA2R398W were impaired, Furthermore, dominant negative effects of GATA2R398W against co-existing intact GATA2 were also observed on a specific Cis-element configuration. Above molecular character of GATA2R398W enabled to elucidate a part of pathogenesis of diseases with heterozygous GATA2 mutation.

Free Research Field

分子血液学

Academic Significance and Societal Importance of the Research Achievements

本変異マウスにおけるB細胞減少を始めとした免疫系異常は、従来用いられてきたGATA2ノックアウトマウスでは見出されてこなかった。本研究より血球分化制御におけるGATA2の新たな役割を見出した。さらに疾患患者と同様にヘテロ接合で表現型を示す本マウスは、GATA2の多様な機能、特に本変異体で特徴的なドミナントネガティブ作用を解析可能な重要な動物モデルとなる。
疾患保因者は、加齢に伴い進行する免疫機能低下や骨髄増殖性腫瘍発症の逃れ得ない恐怖に対峙しなければならない。新規治療薬につながる標的分子の発見や悪性化の効果的な予防法の開発を目指した基礎研究を、本研究成果により加速させることができると考える。