JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα

Self Cite

234

260

Section: Discussionmentioning

confidence: 99%

Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis

Marty

Pecquet

Nivarthi

et al. 2016

Self Cite

234

260

“…The Li 2010 model presented with fewer phenotypic HSCs that were compromised in their reconstitution ability and self-renewal and had accumulated DNA damage, 20,34 whereas the Mullaly 2010 model observed no impact on HSC competitiveness despite an altered cycling status. 36,37 In the Marty 2010 model, an increase in HSC competitiveness was reported, 33 whereas the Tiedt 2008 model showed a complex HSC phenotype with an increase of phenotypic long-term HSCs that were less competitive, expressed a short-term HSC gene signature, and presented with an increase in DNA damage. 35 Using the Li et al and Kent et al models, 20,21,34 in which a HSC defect had been observed, it was striking to see that nascent HSCs are completely unaffected by the JAK2V617F mutation, even when present in 2 copies.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of the JAK2V617F mutation on HSCs has been studied 20,21,[33][34][35][36][37] and was shown to compromise HSC function in one model, 20,34 a defect that is even more severe when homozygous. 21 Using the model, in which JAK2V617F is expressed from the mouse endogenous Jak2 locus following recombination with Stella-Cre, 21 we set out to determine how constitutively active JAK2 would affect embryonic HSPCs.…”

Section: Agm Hscs Are Resistant To the Effects Of The Jak2v617f Mutationmentioning

confidence: 99%

Analysis of Jak2 signaling reveals resistance of mouse embryonic hematopoietic stem cells to myeloproliferative disease mutation

Mascarenhas

Bacon

Kapeni

et al. 2016

Key Points• Emerging HSCs require Jak2 and Pi3k signaling for proliferation and survival.• Embryonic HSCs are unaffected by the JAK2V617F mutation.The regulation of hematopoietic stem cell (HSC) emergence during development provides important information about the basic mechanisms of blood stem cell generation, expansion, and migration. We set out to investigate the role that cytokine signaling pathways play in these early processes and show here that the 2 cytokines interleukin 3 and thrombopoietin have the ability to expand hematopoietic stem and progenitor numbers by regulating their survival and proliferation. For this, they differentially use the Janus kinase (Jak2) and phosphatidylinositol 3-kinase (Pi3k) signaling pathways, with Jak2 mainly relaying the proproliferation signaling, whereas Pi3k mediates the survival signal. Furthermore, using Jak2-deficient embryos, we demonstrate that Jak2 is crucially required for the function of the first HSCs, whereas progenitors are less dependent on Jak2. The JAK2V617F mutation, which renders JAK2 constitutively active and has been linked to myeloproliferative neoplasms, was recently shown to compromise adult HSC function, negatively affecting their repopulation and self-renewal ability, partly through the accumulation of JAK2V617F-induced DNA damage. We report here that nascent HSCs are resistant to the JAK2V617F mutation and show no decrease in repopulation or selfrenewal and no increase in DNA damage, even in the presence of 2 mutant copies. More importantly, this unique property of embryonic HSCs is stably maintained through ‡1 round of successive transplantations. In summary, our dissection of cytokine signaling in embryonic HSCs has uncovered unique properties of these cells that are of clinical importance.

“…Cell numbers in the body were calculated by summing estimated numbers in whole-body BM and in the spleen, as previously described. 34,35 (A) Compared with WT mice, TET2KD mice and double-mutant mice showed increased BM-LSK frequencies, and JAK2V617F mice showed decreased spleen-LSK frequencies; JAK2V617F and double-mutant mice showed increased BM-LK frequencies and spleen-LK frequencies. (B) Compared with WT mice, JAK2V617F mice showed decreased nucleated cells in the femur, spleen, and body.…”

mentioning

confidence: 99%

Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator

Kameda¹,

Shide²,

Yamaji³

et al. 2015

Key Points• Loss of TET2 accelerates the degree of malignancy of MPNs in combination with JAK2V617F.• Loss of TET2 sustains MPNs in combination with JAK2V617F.Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed primary myelofibrosis-like features; the addition of loss of TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double-mutant (JAK2V617F plus loss of TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss of TET2 developed and maintained MPNs in the second recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In-vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long-term, but concurrent loss of TET2 mutation restored it. Transcriptional profiling revealed that loss of TET2 affected the expression of many HSC signature genes. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F. (Blood. 2015;125(2):304-315) IntroductionMyeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and a gradual expansion of malignant intramedullary/extramedullary hematopoiesis. Mutations in Janus kinase 2 (JAK2), 1-4 myeloproliferative leukemia protein, 5 and the recently reported calreticulin 6,7 are considered to play a "driver" role in MPNs. JAK2 mutations (eg, JAK2V617F and JAK2 exon 12 mutations) are the most frequent of these; almost all polycythemia vera (PV) patients and about half of essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients have these mutations. [1][2][3][4]8,9 JAK2V617F mutations induce the phosphorylation of Janus kinases and signal transducers and activators of transcription (STATs) in cytokine-dependent cell lines without cytokine stimulation, and contribute to autonomous cell growth.1,4 JAK2V617F leads to MPNs in all transgenic [10][11][12] or knockin mouse 13-16 models, and is thought to play a central role in MPN development.In addition to the above driver mutations, mutations in epigenetic regulators such as TET2, DNMT3A, ASXL1, EZH2, and IDH1/2 have been reported. 17 Of these, TET2, a methylcytosine dioxygenase that converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC), [18][19][20] is mutated in chronic-phase MPNs, specifically in 10% to 17% of PV, 4% to 11% of ET, and 8% to 25% of PMF. [21][22][23] TET2 is also mutated in 13% to 32% of blastic-phase MPNs and is invol...