Overview of transgenic mouse models of myeloproliferative neoplasms (MPNs) Journal Article
| Authors: | Dunbar, A.; Nazir, A.; Levine, R. |
| Article Title: | Overview of transgenic mouse models of myeloproliferative neoplasms (MPNs) |
| Abstract: | Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases characterized by aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. In 2005, seminal work by multiple groups identified the JAK2V617F mutation in a significant fraction of MPN patients. Since that time, murine models of JAK2V617F have greatly enhanced the understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and have provided an in vivo pre-clinical platform that can be used to develop novel therapies. From early retroviral transduction models to transgenics, and ultimately conditional knock-ins, murine models have established that JAK2V617F alone can induce an MPN-like syndrome in vivo. However, additional mutations co-occur with JAK2V617F in MPNs, often in proteins involved in epigenetic regulation that can dramatically influence disease outcomes. In vivo modeling of these mutations in the context of JAK2V617F has provided additional insights into the role of epigenetic dysregulation in augmenting MPN hematopoiesis. In this overview, early murine model development of JAK2V617F is described, with an analysis of its effects on the hematopoietic stem/progenitor cell niche and interactions with downstream signaling elements. This is followed by a description of more recent in vivo models developed for evaluating the effect of concomitant mutations in epigenetic modifiers on MPN maintenance and progression. Mouse models of other driver mutations in MPNs, including primarily calreticulin (CALR) and Tpo-receptor (MPL), which occur in a significant percentage of MPN patients with wild-type JAK2, are also briefly reviewed. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc. |
| Keywords: | signal transduction; myeloproliferative disorders; leukemia; genetics; mutation; myeloproliferative disorder; janus kinase 2; thrombopoietin receptor; animal; metabolism; animals; gene targeting; cell line, tumor; physiology; transgenic mouse; mice, transgenic; disease model; epigenetics; epigenesis, genetic; tumor cell line; hematopoietic stem cells; hematopoietic stem cell; gene knock-in techniques; disease models, animal; genetic epigenesis; stat protein; jak2 protein, human; calreticulin; receptors, thrombopoietin; jak2; myeloproliferative neoplasms; stat transcription factors; humans; human; calreticulin, human |
| Journal Title: | Current Protocols in Pharmacology |
| Volume: | 77 |
| ISSN: | 1934-8282 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2017-06-01 |
| Start Page: | 14.40.1 |
| End Page: | 14.40.19 |
| Language: | English |
| DOI: | 10.1002/cpph.23 |
| PUBMED: | 28640953 |
| PROVIDER: | scopus |
| PMCID: | PMC6352313 |
| DOI/URL: | |
| Notes: | Review -- Export Date: 2 August 2017 -- Source: Scopus |
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