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Lessons from mouse models of MPN
International Review of Cell and Molecular Biology Pub Date : 2021-04-09 , DOI: 10.1016/bs.ircmb.2021.02.009
Camelia Benlabiod 1 , Tracy Dagher 1 , Caroline Marty 1 , Jean-Luc Villeval 1
Affiliation  

Over the past decades, a variety of MPN mouse models have been developed to express in HSC the main mutations identified in patients: JAK2V617F, CALRdel52 or ins5 and MPLW515L. These models mimic quite faithfully human PV or ET with their natural evolutions into MF and their hemostasis complications, demonstrating the driver function of these mutations in MPN. Here, we review these models and show how they have improved our general understanding of MPN regarding (1) the mechanisms of fibrosis, thrombosis/hemorrhages and disease initiation, (2) the roles of additional mutations and signaling pathways in disease progression and (3) the preclinical development of novel therapies. We also address controversial results between these models and remind how these models may differ from human MPN onset and also how basically mice are not humans, encouraging caution when one draw lessons from mice to humans. Furthermore, the contribution of germline genetic predisposition, HSC and niche aging, metabolic, oxidative, replicative or genotoxic stress, inflammation, immune escape and additional mutations need to be considered in further investigations to encompass the full complexity of human MPN in mice.



中文翻译:

MPN 小鼠模型的经验教训

在过去的几十年中,已经开发了多种 MPN 小鼠模型来在 HSC 中表达在患者中发现的主要突变:JAK2 V617FCALRdel52ins5MPL W515L. 这些模型非常忠实地模拟了人类 PV 或 ET,它们自然演变为 MF 及其止血并发症,证明了这些突变在 MPN 中的驱动功能。在这里,我们回顾了这些模型,并展示了它们如何提高我们对 MPN 的一般理解,包括 (1) 纤维化、血栓形成/出血和疾病起始的机制,(2) 其他突变和信号通路在疾病进展中的作用和 (3 ) 新疗法的临床前开发。我们还解决了这些模型之间有争议的结果,并提醒这些模型与人类 MPN 发病有何不同,以及老鼠基本上不是人类,鼓励人们在从老鼠身上吸取教训时要谨慎。此外,种系遗传易感性、HSC 和生态位老化、代谢、氧化、

更新日期:2021-04-09
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