在T细胞急性淋巴细胞白血病中,TAL1劫持了MYCN增强剂,诱导MYCN表达和依赖于梅瓦酸途径
Shi Hao Tan1, Tze King Tan1, Rui Yokomori1
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Leukemia
|August 17, 2023
概括
在T细胞急性淋巴细胞白血病 (T-ALL) 中由TAL1驱动的失调的MYCN瘤基因表达,造成了脆弱性. 抑制甲基酸通路酶HMGCR显示出对T-ALL治疗的前景.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学是一种遗传学.
背景情况:
- T细胞急性淋巴细胞白血病 (T-ALL) 的特征是异常的转录因子 (TF) 表达,包括TAL1,NOTCH1和MYC.
- 这些TFs破坏正常的基因表达,驱动白血病发生.
研究的目的:
- 识别和描述T-ALL.中的癌基因的新型调控元素.
- 调查MYCN在T-ALL病变发生中的功能作用.
- 在已识别的监管途径中探索潜在的治疗点.
主要方法:
- 鉴定一种调节MYCN表达的保存增强元件 (enhMYCN).
- 在T-ALL细胞系和异种移植模型中评估MYCN依赖性.
- 基因表达与美瓦酸途径相关的分析.
- 对抑制HMG-CoA减少酶 (HMGCR) 的敏感度的评估.
主要成果:
- 一种进化保守的增强剂,enhMYCN,在T-ALL.中被TAL1异常激活.
- 有TAL1阳性的T-ALL细胞在生存过程中严重依赖MYCN.
- MYCN对美酸盐路径中的基因进行上调,使T-ALL细胞对HMGCR抑制敏感.
- MYC和MYCN表现出功能冗余,表明T-ALL的双重依赖.
结论:
- 通过 enhMYCN 来激活TAL1介导的MYCN对T-ALL至关重要.
- TAL1-MYCN-HMGCR轴代表了T-ALL.的潜在治疗策略.
- 针对HMGCR为T-ALL治疗提供了一个有希望的途径,原因是途径依赖性.
相关概念视频
01:06Induced Pluripotent Stem Cells
4.2K
Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
Somatic...
4.2K
02:23Abnormal Proliferation
4.6K
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...
4.6K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
02:23Master Transcription Regulators
6.9K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.9K
02:38Mitogens and the Cell Cycle
6.6K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K
02:54Canonical Wnt Signaling Pathway
8.8K
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...
8.8K