Aberrant signal transduction pathways in myeloproliferative neoplasms

Kota, Janaiah; Caceres, Nancy E.; Constantinescu, Stefan N.

doi:10.1038/leu.2008.236

Cited by 60 publications

(58 citation statements)

References 152 publications

(168 reference statements)

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“…These findings show that STAT3 serine phosphorylation is mainly involved in enhancing LAP expression in Jak2 V617F signalling pathways. JAK2 V617F mutation occurs at the HSC level (Jamieson et al, 2006;Kota et al, 2008). It is still unclear how this common mutation can induce three distinct MPN.…”

Section: Discussionmentioning

confidence: 99%

JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation

et al. 2010

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SummaryThe acquired JAK2 V617F mutation is observed in the majority of patients with BCR‐ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR‐ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild‐type Jak2. We found that Jak2 V617F mutation, but not wild‐type Jak2 enhanced LAP expression in NB4‐derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.

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Section: Discussionmentioning

confidence: 99%

JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation

et al. 2010

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“…Hematopoietic cells of ∆Hmga2 mice also showed high expressions of Jak2 mRNA and phosphorylated Stat3 or Akt 29) , suggesting that constitutive JAK2 -STAT3 and AKT activations induced by overexpression of HMGA2 may play a role in proliferative hematopoiesis. Although it should be investigated in the future how the expression of HMGA2 correlates with these pathways, it might contribute to activation of some signaling pathways shown in hematopoietic cells even without JAK2 mutation of some MPN patients 30) . Interestingly, it has been reported that HMGA2 upregulation was more apparent in JAK2V617F + than JAK2V617F − cases in PMF 25) .…”

Section: Discussionmentioning

confidence: 99%

“…JAK2V617F + hematopoietic cells fail to repopulate in competitive repopulation assays using some JAK2V617F knockin model animals 16,17) and in a coincidental human hematopoietic stem cell transplantation from JAK2V617F + idiopathic portal hypertension patient to a patient with MDS 39) . Moreover, even without a mutation in JAK2, MPL, or other signaling -related genes, a signaling involving JAK -STAT pathway are generally activated in MPN hematopoiesis, in which the cause of signaling activation is largely unknown 30,40,41) . Indeed, erythropoietin -independent erythroid colony formation from progenitor cells with only wild -type JAK2 has been shown 42) .…”

Section: Mutations In Cytokine Signaling -Related Genesmentioning

confidence: 99%

“…Mutations in JAK2, including JAK2V617F, which are the most common genetic abnormality in MPN, lead to phosphorylation of JAK2 tyrosine kinase in hematopoietic cells even in the absence of cytokines 8 - 11) . Following phosphorylation of JAK2, downstream signaling is activated via transcription factors STAT3 and STAT5, MAP kinases, PI3K and AKT 30) . JAK2 kinase has seven homology domains, from JH1 to JH7 and plays a important role in the proliferation of myeloid cells by hematopoietic growth factor cytokines.…”

Section: Mutations In Cytokine Signaling -Related Genesmentioning

confidence: 99%

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The Role of Hmga2 in the Proliferation and Expansion of a Hematopoietic Cell in Myeloproliferative Neoplasms

Ikeda¹,

Ogawa²,

Takeishi³

2012

FJMS

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: Philadelphia chromosome -negative myeloproliferative neoplasms (MPN), which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by clonal proliferative hematopoiesis with increased blood cell count. Clonal expansion mechanisms in MPN and related disorders such as myelodysplastic syndromes (MDS) remain to be elucidated. Although mutations in the JAK2 gene lead to a proliferative hematopoiesis in majority of MPN and some MDS, the mutation alone does not cause a clonal expansion. In addition to JAK2 mutations, several genetic abnormalities, including TET2 and polycomb group genes involving epigenetic regulation have been reported in patients with MPN. Moreover, overexpression of HMGA2 due to removal of specific sites in its 3 untranslated region for regulatory let -7 micro RNAs may contribute to the proliferative hematopoiesis with conferring a growth advantage at the level of a hematopoietic stem cell in some cases with MPN.

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“…Most work has been described in cell lines or in animal model systems, in which JAK2 and MPL mutations activate the STAT5, STAT3, PI-3K/AKT, and RAS-MAPK-ERK pathways. 4,8,9 However, these model systems may not adequately reflect the cellular context or the molecular complexity of human MPNs. In addition, where patient material has been used, technical aspects, such as the use of intervening in vitro culture conditions that do not reflect the proper in vivo milieu or the analysis of highly heterogeneous populations of cells using Western blotting or immunohistochemistry of fixed trephine sections, may limit the interpretation of these experiments.…”

Section: Introductionmentioning

confidence: 99%

Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms

Anand

Stedham

Gudgin

et al. 2011

Blood

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Myeloproliferative neoplasms (MPNs) are associated with recurrent activating mutations of signaling proteins such as Janus kinase 2 (JAK2). However, the actual downstream signaling events and how these alter myeloid homeostasis are poorly understood. We developed an assay to measure basal levels of phosphorylated signaling intermediates by flow cytometry during myeloid differentiation in MPN patients. Our study provides the first systematic demonstration of specific signaling events and their comparison with disease phenotype and JAK2 mutation status. We demonstrate increased basal signaling in MPN patients, which occurs in both early and later stages of myeloid differentiation. In addition, the pattern of signaling is not correlated with JAK2 mutation status and signaling intensity is poorly correlated with mutant JAK2 allele burden. In contrast, signaling differences are detected between different MPN disease phenotypes. Finally, we demonstrate that signaling can be inhibited by a JAK2-selective small molecule, but that this inhibition is not JAK2 V617F specific, because MPN patients with mutant JAK2, wild-type JAK2, and control patients were inhibited to a similar degree. Our data suggest that, in addition to JAK2 mutations, other factors contribute significantly to the MPN phenotype, results that are relevant to both the pathogenesis and therapy of MPN. (Blood. 2011;118(6): 1610-1621)

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Aberrant signal transduction pathways in myeloproliferative neoplasms

Cited by 60 publications

References 152 publications

JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation

JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation

The Role of Hmga2 in the Proliferation and Expansion of a Hematopoietic Cell in Myeloproliferative Neoplasms

Increased basal intracellular signaling patterns do not correlate with JAK2 genotype in human myeloproliferative neoplasms

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