ABCC4影响巨核细胞生成并保护巨核细胞免受6-巯基嘌呤诱导的细胞毒性

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Sabina Ranjit , Yao Wang , Jingwen Zhu , Satish B. Cheepala , Erin G. Schuetz , Woo Jung Cho , Beisi Xu , Camenzind G. Robinson , Gang Wu , Anjaparavanda.P. Naren , John D. Schuetz
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引用次数: 0

摘要

ABCC4是一种ATP结合盒转运蛋白,在血小板形成、巨核细胞生成过程中的作用尚不清楚。在这里,我们发现ABCC4在巨核细胞(MKs)中高度表达。对公共基因组数据(ATAC-seq和全基因组染色质相互作用,Hi-C)的挖掘表明,关键的巨核细胞生成转录因子(TF)与ABCC4调控元件相互作用,可能是MKs中ABCC4高表达的原因。重要的是,ABCC4的这些基因组相互作用的排名高于在巨核生成中具有已知作用的基因,这表明ABCC4在巨核形成中的作用。然后,我们证明ABCC4是最佳血小板形成所必需的,因为来自ABCC4-/-小鼠的胎肝衍生MKs的体外分化表现出血小板形成和多倍体化受损,这是最佳巨核生成所必需的特征。同样,人类巨核母细胞系MEG-01显示,急性ABCC4抑制显著抑制了巨核生成的关键过程,这些作用与减少cAMP输出和增强巨核生成负调节因子蛋白激酶a(PKA)从ABCC4的解离有关。ABCC4抑制后PKA活性同时增加,同时GATA-1表达显著降低,这是最佳巨核细胞生成所需的TF。此外,ABCC4保护MKs免受6-巯基嘌呤(6-MP)的影响,因为ABCC4-/-小鼠在6-MP治疗后MKs显著减少。总之,我们的研究表明,ABCC4不仅保护MKs,而且是MKs最大限度地生产血小板所必需的,这表明调节ABCC4功能可能是调节血小板生产的潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ABCC4 impacts megakaryopoiesis and protects megakaryocytes against 6-mercaptopurine induced cytotoxicity

The role of ABCC4, an ATP-binding cassette transporter, in the process of platelet formation, megakaryopoiesis, is unknown. Here, we show that ABCC4 is highly expressed in megakaryocytes (MKs). Mining of public genomic data (ATAC-seq and genome wide chromatin interactions, Hi-C) revealed that key megakaryopoiesis transcription factors (TFs) interacted with ABCC4 regulatory elements and likely accounted for high ABCC4 expression in MKs. Importantly these genomic interactions for ABCC4 ranked higher than for genes with known roles in megakaryopoiesis suggesting a role for ABCC4 in megakaryopoiesis. We then demonstrate that ABCC4 is required for optimal platelet formation as in vitro differentiation of fetal liver derived MKs from Abcc4-/- mice exhibited impaired proplatelet formation and polyploidization, features required for optimal megakaryopoiesis. Likewise, a human megakaryoblastic cell line, MEG-01 showed that acute ABCC4 inhibition markedly suppressed key processes in megakaryopoiesis and that these effects were related to reduced cAMP export and enhanced dissociation of a negative regulator of megakaryopoiesis, protein kinase A (PKA) from ABCC4. PKA activity concomitantly increased after ABCC4 inhibition which was coupled with significantly reduced GATA-1 expression, a TF needed for optimal megakaryopoiesis. Further, ABCC4 protected MKs from 6-mercaptopurine (6-MP) as Abcc4-/- mice show a profound reduction in MKs after 6-MP treatment. In total, our studies show that ABCC4 not only protects the MKs but is also required for maximal platelet production from MKs, suggesting modulation of ABCC4 function might be a potential therapeutic strategy to regulate platelet production.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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