Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function.

IF 3.1 3区 医学 Q2 HEMATOLOGY
Current Opinion in Hematology Pub Date : 2023-07-01 Epub Date: 2023-04-27 DOI:10.1097/MOH.0000000000000763
Kirby D Johnson, Mabel M Jung, Vu L Tran, Emery H Bresnick
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引用次数: 0

Abstract

Purpose of review: Recent discoveries have provided evidence for mechanistic links between the master regulator of hematopoiesis GATA2 and the key component of interferon and innate immunity signaling pathways, interferon-regulatory factor-8 (IRF8). These links have important implications for the control of myeloid differentiation in physiological and pathological states.

Recent findings: GATA2 deficiency resulting from loss of the Gata2 -77 enhancer in progenitors triggers an alarm that instigates the transcriptional induction of innate immune signaling and distorts a myeloid differentiation program. This pathological alteration renders progenitors hyperresponsive to interferon γ, toll-like receptor and interleukin-6 signaling and impaired in granulocyte-macrophage colony-stimulating factor signaling. IRF8 upregulation in -77-/- progenitors promotes monocyte and dendritic cell differentiation while suppressing granulocytic differentiation. As PU.1 promotes transcription of Irf8 and other myeloid and B-lineage genes, GATA2-mediated repression of these genes opposes the PU.1-dependent activating mechanism.

Summary: As GATA2 deficiency syndrome is an immunodeficiency disorder often involving myelodysplastic syndromes and acute myeloid leukemia, elucidating how GATA2 commissions and decommissions genome activity and developmental regulatory programs will unveil mechanisms that go awry when GATA2 levels and/or activities are disrupted.

干扰素调节因子-8 依赖性先天免疫警报感知 GATA2 缺乏,从而改变造血分化和功能。
综述的目的:最近的发现为造血主调节因子 GATA2 与干扰素和先天性免疫信号通路的关键成分干扰素调节因子-8(IRF8)之间的机理联系提供了证据。这些联系对于在生理和病理状态下控制髓系分化具有重要意义:祖细胞中 Gata2 -77 增强子缺失导致的 GATA2 缺乏会触发警报,诱发先天性免疫信号的转录诱导,并扭曲髓系分化程序。这种病理改变使祖细胞对干扰素γ、toll样受体和白细胞介素-6信号反应过度,并损害粒细胞-巨噬细胞集落刺激因子信号。IRF8 在-77-/-祖细胞中的上调促进了单核细胞和树突状细胞的分化,同时抑制了粒细胞的分化。小结:GATA2缺乏综合征是一种免疫缺陷疾病,常涉及骨髓增生异常综合征和急性髓系白血病,阐明GATA2如何委托和解除委托基因组活性和发育调控程序,将揭示GATA2水平和/或活性被破坏时出现问题的机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.60
自引率
3.10%
发文量
78
审稿时长
6-12 weeks
期刊介绍: ​​​​​​​​Current Opinion in Hematology is an easy-to-digest bimonthly journal covering the most interesting and important advances in the field of hematology. Its hand-picked selection of editors ensure the highest quality selection of unbiased review articles on themes from nine key subject areas, including myeloid biology, Vascular biology, hematopoiesis and erythroid system and its diseases.
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