降低PRC2功能会通过降低WNT通路活性导致T-ALL中阿斯巴拉金酶耐药性
Thomas Lefeivre1,2, Theodora-Ioana Grosu1,2, Cosmin Tudose1,2,3
1Systems Biology Ireland, University College Dublin, Dublin, Ireland.
Blood advances
|February 24, 2026
概括
在T细胞急性淋巴细胞白血病 (T-ALL) 中,多抑制复合体2 (PRC2) 的丧失通过改变WNT/STOP信号来降低阿斯巴拉基纳斯的敏感性. 蛋白质酶抑制可以克服这种抗性.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 癌症生物学 癌症生物学
- 分子瘤学分子瘤学
背景情况:
- 聚抑制复合体2 (PRC2) 的功能丧失突变与T细胞急性淋巴细胞白血病 (T-ALL) 治疗反应不佳有关.
- 由于PRC2的变化导致的T-ALL疗法耐药性背后的机制尚不清楚.
研究的目的:
- 研究PRC2变化如何影响T-ALL中的信号通路.
- 确定这些途径的变化是否会影响对白血病治疗的反应.
主要方法:
- 利用同源的T-ALL细胞模型和初级患者数据.
- 综合转录组,蛋白组和蛋白组分析.
- 与患者的转录资料相关联的发现.
主要成果:
- PRC2缺乏,特别是EZH2损失,显著降低了WNT依赖蛋白质稳定 (WNT/STOP) 途径的活动.
- 失去PRC2显著降低了对阿斯巴拉金酶的敏感性,这是T-ALL治疗的关键.
- 这种耐药性与细胞无处不在的增加和由于WNT/STOP抑制而增加的氨酸储量有关.
- 在PRC2-贫乏的T-ALL中,阿斯巴拉金酶耐药性与患者数据相关,并且可以通过蛋白质酶抑制来减轻.
结论:
- 通过抑制WNT/STOP通路和改变细胞新陈代谢,PRC2损失使T-ALL中产生原酶耐药性.
- 制药性蛋白酶体抑制是一种潜在的策略,可以克服PRC2-突变T-ALL.在PRC2-突变T-ALL.中抗阿斯巴拉金酶的抗性.
- 了解这些机制为改善诱导治疗结果提供了潜在的途径.
相关概念视频
01:19Allosteric Proteins-ATCase
6.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.7K
02:54Canonical Wnt Signaling Pathway
10.8K
The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
10.8K
01:41Non-Canonical Wnt Signaling Pathways
8.5K
Wnt is a zygotic effect gene that is expressed during very early embryonic development. It regulates various processes in animals starting from early development through the adult stage, such as organogenesis in the embryo and maintenance of neuronal and blood stem cells. Wnt proteins can induce a wide variety of intracellular pathways depending upon the specific abilities of different Wnt ligands to form a complex with shared and cognate receptors in the presence of different co-receptors. The...
8.5K
02:23Abnormal Proliferation
5.3K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.3K
01:09GPCRs Regulate Adenylyl Cylase Activity
7.8K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
7.8K
01:12GPCR Desensitization
8.4K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
8.4K