The role of driver mutations in myeloproliferative neoplasms: insights from mouse models
- PDF / 1,072,643 Bytes
- 11 Pages / 595.276 x 790.866 pts Page_size
- 53 Downloads / 163 Views
PROGRESS IN HEMATOLOGY Progress in elucidation of molecular pathophysiology and its application to therapeutic decisions of MPNs
The role of driver mutations in myeloproliferative neoplasms: insights from mouse models Kotaro Shide1 Received: 28 May 2019 / Revised: 11 December 2019 / Accepted: 12 December 2019 © Japanese Society of Hematology 2019
Abstract High frequency of JAK2V617F or CALR exon 9 mutations is a main molecular feature of myeloproliferative neoplasms (MPNs). Analysis of mouse models driven by these mutations suggests that they are a direct cause of MPNs and that the expression levels of the mutated genes define the disease phenotype. The function of MPN-initiating cells has also been elucidated by these mouse models. Such mouse models also play an important role in modeling disease to investigate the effects and action mechanisms of therapeutic drugs, such as JAK2 inhibitors and interferon α, against MPNs. The mutation landscape of hematological tumors has already been clarified by next-generation sequencing technology, and the importance of functional analysis of mutant genes in vivo should increase further in the future. Keywords Myeloproliferative neoplasms · Mouse models · JAK2 · CALR
Significance of generating mouse models With the widespread adoption of next-generation sequencing technology, we have entered the final stages of understanding the overall picture of the genetic mutations in blood tumors. Numerous genetic mutations in various tumor cells have been identified, and a highly frequent mutation specific to a disease is likely to be a “driver mutation” that directly causes the development and progression of the tumor. If a mouse model introduced with such a mutation develops a tumor resembling that of humans, then it directly proves that the mutation is indeed a driver mutation. With mouse models, we can also observe the long-term effects of the mutant gene at the individual level. Mutations in hematopoietic stem cells (HSCs) have been shown to affect blood cell differentiation and to potentially result in a growth advantage over normal HSCs. A system that can mimic human tumors can be used as a disease model to evaluate novel therapeutic methods. * Kotaro Shide [email protected]‑u.ac.jp 1
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889‑1692, Japan
Thus, mouse models are powerful tools for elucidating the mechanism of onset and for developing novel therapeutic methods.
Driver mutations in myeloproliferative neoplasms The term myeloproliferative neoplasms (MPNs) is commonly used to describe polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Table 1 lists the notable driver mutations of MPNs. A mutation in janus kinase 2 (JAK2) substitutes the 617th amino acid from valine (V) to phenylalanine (F) (accordingly termed JAK2V617F mutation) and is observed in at least 95% of patients with PV and 60% of patients with ET and PMF [1–5]. JAK2 is a tyrosine kinas
Data Loading...
