Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing <i>JAK2</i>-V617F

Lundberg, Pontus; Takizawa, Hajime; Kubovčáková, Lucia; Guo, Guoji; Hao-Shen, Hui; Dirnhofer, Stephan; Orkin, Stuart H.; Manz, Markus G.; Skoda, Radek C.

doi:10.1084/jem.20131371

Cited by 90 publications

(82 citation statements)

References 64 publications

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“…Furthermore, it cannot be ruled out whether an inherited mutation in one of the alleles may be accompanied by an epigenomic inactivation of the other otherwise normal alleles rendering the cell biological homozygous. What seems clear, however, and the present data contributes to this conclusion, is that the role of the JAK2 V617F mutation in the pathogenicity of the different MPNs may differ amongst different MPNs requiring the JAK2 V617F mutation more often than others (e.g., ET vs. PV), which would indicate other oncogenic mutations that may be relevant for certain cases others than JAK2 V617F (16,33,58,59).…”

Section: Discussionmentioning

confidence: 54%

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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Abstract. Myeloproliferative neoplasms (MPNs) result from the malignant transformation of a hematopoietic stem-cell (HSC), leading to abnormal amplification and proliferation of myeloid lineages. Identification of the Janus kinase 2 (JAK2) V617F mutation developed the knowledge of Philadelphia-negative (PN)-MPNs, contributing to and influencing the definition of the phenotype and prognostic impact. Considering the lack of Portuguese epidemiological data, the present study intends to characterize the prevalence of the JAK2 mutation in a PN-MPN versus a control Portuguese population. Caucasian Portuguese PN-MPN patients (n=133) and 281 matched control subjects were investigated. No significant differences were identified between the case and control groups concerning age distribution or smoking habits. Pathology distribution was as follows: 60.2% with essential thrombocythemia (ET), 29.3% with polycythemia vera (PV) and 10.5% with primary myelofibrosis (PMF). A total of 75.0% of patients were positive for the presence of the JAK2 V617F mutation. In addition, the prevalence of PV was 87.2%, ET was 73.4% and PMF was 50.0%. The JAK2 V617F mutation is observed in various MPN phenotypes, and has an increased incidence in ET patients and a decreased incidence in PV patients. These data may contribute to improving the knowledge of the pathophysiology of these disorders, and to a more rational and efficient selection of therapeutic strategies to be adopted, notably because most of the patients are JAK2 V617F negative.

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Section: Discussionmentioning

confidence: 54%

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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“…30 Finally, it is likely that there is functional heterogeneity within the JAK2-mutated HSC pool and across disease subtypes. For instance, there is evidence that the ability to self-renew, and therefore stably engraft, may decrease with increasing levels of JAK2 expression, 31 similar to the differences in stem cell behavior seen at different expression levels of STAT5 32 and oncogenic NRAS.…”

Section: Cellular Consequences Of Jak2 Mutationsmentioning

confidence: 89%

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

2016

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“…Transplantability of JAK2V617F-associated disease has been demonstrated 20,21,35 ; however, no changes in platelets, hematocrit, hemoglobin, or white blood cell counts were observed in recipients of heterozygous or homozygous AGMs, even when repopulated at high levels, demonstrating that embryonic HSCs do not initiate a myeloproliferative disease (Figure 6F-I).…”

Section: /Vfmentioning

confidence: 91%

“…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%

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

Mascarenhas

Bacon

Kapeni

et al. 2016

Blood

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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.

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Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F

Abstract: Lundberg et al. show that a single hematopoietic stem cell carrying a mutation in JAK2 is able to initiate cancer in mice by promoting cell division and maintaining self-renewal.

Cited by 90 publications

References 64 publications

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

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

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