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.

Metabolic Vulnerabilities and Epigenetic Dysregulation in Myeloproliferative Neoplasms

“…Activating mutations in MPL are present in ∼ 2% to 4% of ET patients and ~ 3% to 5% of PMF patients ( 6 , 8 ). These mutations are designated drivers of human MPN in part because they induce MPN phenotypes in mouse models ( 9 – 11 ). As a common signaling event induced by MPN driving mutations, JAK2 activation is the critical signaling node in MPN, with MPL playing a requisite role in driving myeloproliferation driven by mutant JAK2 and CALR ( 12 – 18 ).…”

Experimental Modeling of Myeloproliferative Neoplasms

“…Several mouse models have been created to characterize the role of aberrant Jak2 signaling within the hematopoietic compartment. Retroviral transduction models, transgenic and knock-in mice bearing Jak2 V617F concomitantly with epigenetic modifier mutations were used to study MPN maintenance and progression (reviewed elsewhere in detail [58]). The early retroviral transduction models [59,60,61,62] confirmed the role of mutated Jak2 protein in MPN pathology, in which all mice developed a PV-like disease with noticeable erythrocytosis, leukocytosis, and splenomegaly, demonstrating that the Jak2 V617F mutation is sufficient to induce an MPN-like condition in mice.…”

“…The more advanced transgenic mouse models allowing quantitative expression of Jak2 V617F [48,63,64] indicated a correlation between the mutant Jak2 protein expression levels and MPN phenotypes progressing from ET to PV and PMF with increasing Jak2 V617F allelic burden, thus emulating the continuous progression in MPN sub-types. In 2010, four independent groups recreated Jak2 V617F expression in the bone marrow compartment through knock-in models with Cre-mediated recombination under the control of a specific hematopoietic promoter [58]. These mice allowed the impact of Jak2 mutation to be studied in its endogenous environment with the native expression ratio.…”

“…Detailed analysis of double-mutant early stem cells (so-called LSK, Lin − Sca1 + cKit + ) showed a strong competitive advantage over wild-type cells, suggesting that mutated Tet2 cooperates with Jak2 V617F in vivo to promote stem cell self-renewal and proliferation while enhancing production of late-stage stem/progenitors and resulting in disease progression through combinatorial effects [70,71]. Similar to Tet2 , mouse models combining the loss-of-function mutation of Ezh2 with Jak2 V617F developed an aggressive MPN-like phenotype with an overall expansion of the LSK stem/progenitor compartment [58].…”

“…In addition, these results have demonstrated that the Mpl W515L clone relies on the presence of wild-type Jak2 kinase to maintain the MPN phenotype and vice versa, that wild-type Mpl is indispensable in the development of Jak2 V617F MPN-like diseases in mice. The mouse models with mutated Calr cover the two most commonly seen mutations in humans, CALR del52 and CALR ins5 [86], and are consistent with the ET phenotype in humans—all the models displayed isolated thrombocytosis with no significant effect on erythrocyte or leukocyte counts [58].…”