Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice

Abstract

The Jak2 V617F mutation is found in most classical BCR/ABL-negative myeloproliferative neoplasms (MPNs). Usually, heterozygosity of the mutation is associated with essential thrombocythemia (ET) and homozygosity with polycythemia vera (PV). Retrovirally transduced or transgenic animal models have shown that the mutation is sufficient for MPN development but that the level of expression is crucial for MPN phenotypes. Therefore we investigated the effect of an endogenous heterozygous expression of Jak2 V617F in knock-in (KI) mice. These animals displayed constitutive JAK2 activation and autonomous erythroid progenitor cell growth. Mice suffered from marked polycythemia, granulocytosis and thrombocytosis. Spleens and marrows displayed myeloid trilineage hyperplasia. Most animals survived to develop advanced fibrosis in these organs at around 9 months of age. In conclusion, constitutive heterozygous expression of JAK2 V617F in mice is not embryo-lethal but results in severe PV-like disease with secondary myelofibrosis and not in ET-like disease as expected from patient study. (Blood. 2010; 116(5):783-787)

Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms

“…These findings are also in consonance with functional differences between human PV and MF V617F mutant HSCs as detected in xenotransplant experiments. 18 Furthermore, the in vivo terminal expansion we demonstrate entirely corroborates the results in murine models [12][13][14] and human MPNs in vitro, where PV and ET patients demonstrated erythroid expansion compared with normal controls after long-term CD34 ϩ cell culture experiments. 19 We also demonstrate, using a novel PCR-based assay, that in individual patients the JAK2 V617F homozygous clone has a competitive advantage over the heterozygous clone and that the heterozygous clone does not significantly expand in vivo.…”

“…2,[5][6][7][8][9] Recently, several groups have reported murine models of JAK2 V617F MPN. [10][11][12][13][14] However, the effects of JAK2 V617F expression on hematopoietic stem and progenitor cell (HSPC) homeostasis were not consistent, with the reports of Mullaly et al 14 and Li et al 12 suggesting a neutral or detrimental effect on HSPC compartment size and/or function, whereas Akada et al reported HSPC expansion. 11 In MPN patients, the consequences of JAK2 V617F expression for HSPC compartment homeostasis and later myeloid differentiation are largely unknown.…”

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

“…37 Jak2 V617F transgenic mice displayed ET-like phenotypes 38 and constitutive Stat5 phosphorylation was observed in Jak2 V617F knock-in mice with megakaryocyte hyperplasia and thrombocythemia. 39 In addition, our in-vitro study showed that activation of Jak signaling suppressed the endogenous caspase activation with increases in Mcl-1 and Bcl-xL. These findings suggest that increases in these anti-apoptotic proteins via activation of Jak signaling might be involved in the excessive megakaryocyte survival of ET patients.…”

Impact of isolated germline JAK2V617I mutation on human hematopoiesis

“…17 Mouse models of JAK2V617F expressed from the endogenous genetic loci have provided important insights into JAK2 mutation biology. However, different models of the JAK2V617F mutation have resulted in strikingly heterogeneous phenotypes, with mice primarily developing an essential thrombocythemia phenotype in one model 19 as opposed to polycythemia in others, [20][21][22] and a phenotype that varied according to the ratio of mutant JAK2V617F to wild-type in another model. 23 Moreover, development of myelofibrosis also varied markedly.…”

“…[19][20][21][22][23] Furthermore, these different models have produced conflicting results with regards to the impact of JAK2V617F on hematopoietic stem and progenitor cells, with different models suggesting a suppression, 19 no impact, 20 or expansion of HSCs 21,24 by the JAK2V617F mutation. One proposed explanation for this heterogeneity is that it relates to expression of human 19 versus murine [20][21][22] forms of the JAK2 protein. 4 However, understanding the impact of JAK2 mutation on human hematopoiesis is difficult in MPNs in which the JAK2 mutation may be present in only a subclone that may also have acquired multiple additional and heterogeneous genetic hits.…”