子の作用機序について解析したが，今後は，患者変異型RUNX1が単純な機能欠損や複合体形成不全を起こすだけでなく，野生型RUNX1が形成する発生段階特異的な転写因子複合体の再構築とゲノム上の再配置 (functional conversion)を積極的に阻害することでT前駆細胞の腫瘍化を誘導するという，新しいメカニズムによる腫瘍化の可能性を視野に入れ機能解析を行う予定である．さらに，その異常をコントロールする事でT前駆細胞の腫瘍化を抑制することが出来るか検討し，将来的にはT-ALLの発症メカニズムに基づいた新規治療戦略の創出を目指す．謝 辞本研究にご支援を賜りました公益財団法人 中外創薬科学財団に深く感謝申し上げます．引用文献…1. Hosokawa H and Rothenberg EV: How transcription factors drive choice of T cell fate. Nat Rev Immunol, ― 57 ―21(3): 162-176 (2021).2. Shin B*, Hosokawa H*, Romero-Wolf M, Zhou W, Masuhara K, Tobin V, Levanon D, Groner Y, Rothenberg EV: RUNX1 and RUNX3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching. Proc. Natl. Acad. Sci. USA, 118(4): e2019655118 (2021). *Co-first authors3. Hosokawa H*, Koizumi M, Masuhara K, Romero-Wolf M, Tanaka T, Nakayama T, Rothenberg EV*: Stage-specific action of RUNX1 and GATA3 controls silencing of PU.1 expression in mouse pro-T cells. J Exp Med, 218(8): e20202648 (2021). *Co-corresponding authors4. Hosokawa H*, Romero-Wolf M, Yang Q, Motomura Y, Levanon D, Groner Y, Moro K, Tanaka T, Rothenberg EV*: Cell type specific actions of Bcl11b in early T lineage and group 2 innate lymphoid cells. J Exp Med, 217(1): e20190972 (2020). *Co-corresponding authors5. Hosokawa H, Romero-Wolf M, Yui MA, Ungerback J, Quiloan MLG, Matsumoto M, Nakayama KI, Tanaka T, Rothenberg EV: Bcl11b sets pro T cell fate by site specific cofactor recruitment and by repressing Id2 and Zbtb16. Nat Immunol, 19(12): 1427-1440 (2018).6. Ungerback J*, Hosokawa H*, Wang X, Strid T, Williams BA, Sigvardsson M, Rothenberg EV: Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by SPI1 (PU.1). Genome Res, 28(10): 1508-1519 (2018). *Co-first authors7. Hosokawa H, Ungerback J, Wang X, Matsumoto M, Nakayama, KI, Cohen SM, Tanaka T, Rothenberg EV: Transcription factor PU.1 represses and activates gene expression in early T cells by redirecting partner transcription factor binding. Immunity, 48(6): 1119-1134 (2018).8. Hirano K*, Hosokawa H*, Koizumi M, Endo Y, Yahata T, Ando K, Hozumi K: LMO2 is essential to maintain the ability of progenitors to differentiate into T-cell lineage in mice. eLife, 10: e68227 (2021). *Co-first authors9. Koizumi M, Kama Y, Hirano K, Endo Y, Tanaka T, Hozumi K, Hosokawa H: Transcription factor, Zbtb1, interacts with Lmo2 and maintains the T-lineage differentiation capacity of lymphoid progenitor cells. J Biol Chem, 298(11): 102506 (2022).
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