通过改变受体内部化,CXCL12化学基因二元信号调节了急性骨髓性白血病细胞迁移
Donovan Drouillard1,2, Michael Halyko2,3, Elizabeth Cinquegrani2
1Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee WI, USA.
bioRxiv : the preprint server for biology
|September 10, 2024
概括
一种新的CXCL12变体CXCL12-LD作为部分激动剂,增强了急性髓性白血病 (AML) 细胞中的CXCR4内部化. 这种方法可以克服目前用于AML治疗的CXCR4抑制剂的局限性.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 急性髓性白血病 (AML) 涉及通过CXCL12-CXCR4信号传递保留的类似干细胞的化学抵抗细胞.
- 目前的CXCR4抑制剂可以调动AML细胞,但没有改善存活率,可能是由于持续的受体局部化.
研究的目的:
- 为了描述CXCL12锁定二聚体 (CXCL12-LD) 的信号特性,生物工程CXCL12变体.
- 研究CXCL12-LD作为针对CXCR4在AML中的治疗剂的潜力.
主要方法:
- 对CXCL12-LD结合和下游信号的表征 (G蛋白,β-arrestin,调动).
- 评估CXCL12-LD对AML细胞化学反应和CXCR4内部化的影响.
- 对CXCR4相关化学抵抗基因的AML转录组数据的分析.
- 在小鼠体内研究以评估干细胞动员.
主要成果:
- CXCL12-LD在CXCR4表现出部分激素活性,G蛋白,β-arrestin和信号减少.
- CXCL12-LD抑制了AML细胞化学反应,但增强了CXCR4内部化.
- 具有CXCR4阳性的AML细胞共同表达与化学抵抗和类似爆发状态相关的基因.
- 在小鼠中,CXCL12-LD有效地调动了干细胞.
结论:
- 加强CXCL12-LD的CXCR4内部化可能会规避药理学耐受性.
- 这种部分激素信号提供了一种针对CXCR4在AML中的新策略.
- 对CXCL12-LD的进一步研究可能会为GPCR向改善治疗途径.
相关概念视频
01:21Chemotaxis and Direction of Cell Migration
3.3K
Cells can detect chemical cues in their environment and reorganize the cytoskeleton to migrate toward them or away from them. This directional migration, called chemotaxis, is essential during embryogenesis and development, immune response, tissue repair and regeneration, and reproduction. These chemical cues can either attract or repel the cell's movement. For example, axon development is determined by a combination of chemoattractants and chemorepellents that direct the growing axon...
3.3K
01:09Cell Migration
16.9K
Cell migration, the process by which cells move from one location to another, is essential for the proper development and viability of organisms throughout their life. When cells are not able to migrate properly to their ordained locations, various disorders may occur. For example, disruption in cell migration causes chronic inflammatory diseases such as arthritis.
16.9K
01:32Cytoskeletal Coordination in Cell Migration
4.7K
A migrating cell changes its shape during the cyclic events of attachment and detachment from the substratum and repositions the cell organelles correspondingly. These complex events are orchestrated by the dynamic cytoskeletal network comprising actin filaments, intermediate filaments, and microtubules. Cytoskeletal crosstalk — the direct and indirect communication between the different components — is crucial for this coordination. Direct communication involves various linker...
4.7K
01:21Cell Polarization by Rho Proteins
2.7K
Cell polarity is the asymmetric distribution of cellular and membrane components, making one side of the cell different from the other. This polarity is essential to many processes such as embryogenesis, axon migration, glucose transport across epithelial cells, and directional cell migration. A migrating cell responds to intracellular or extracellular signals via molecular cascades that reorganize the actin cytoskeleton to establish this polarity. In these cells, the Rho family proteins Cdc42,...
2.7K
01:17Intracellular Signaling Affects Focal Adhesions
2.6K
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
2.6K
01:35Cancer Cell Migration through Invadopodia
2.3K
Invadosome is a broad category of cell surface structures with proteolytic activity that degrades the extracellular matrix (ECM). Invadosomes are present in normal cell types, including macrophages, endothelial cells, and neurons, as well as tumor cells. Although the macrophage podosomes and tumor cell invadopodia are classified as invadosomes, they have different structures, molecular pathways, and functions. Podosomes are short structures that last for a few minutes. However,...
2.3K