Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis

Neubauer, Hans; Cumano, Ana; Müller, Mathias; Wu, Hong; Huffstadt, Ulrike; Pfeffer, Klaus

doi:10.1016/s0092-8674(00)81168-x

Cited by 762 publications

(532 citation statements)

References 73 publications

Supporting

Mentioning

515

Contrasting

Unclassified

Order By: Relevance

“…There is also good evidence suggesting essential role for Jak2-STAT5 pathway in erythropoiesis in vitro and in vivo (Wakao et al, 1997;Iwatsuki et al, 1997;Parganas et al 1998;Neubauer et al, 1998). Our preliminary experiments, however, indicated that none of the transgenes used in this study (ras12V, ras17N, and MAPKKm) induced signi®cant alterations in the basal or EPO-induced phosphorylation of endogenous Jak2 protein nor did the ras17N gene a ect the DNAbinding activity of endogenous STAT5 protein (our unpublished observation).…”

Section: Discussionmentioning

confidence: 58%

See 1 more Smart Citation

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

et al. 2000

View full text Add to dashboard Cite

The role of Ras and MAP kinases (MAPKs) in the regulation of erythroid di erentiation was studied using a cell line (SKT6) derived from Friend virus (Anemic strain)-induced murine erythroleukemia. This cell line undergoes di erentiation in vitro in response to erythropoietin (EPO) or other chemical inducers such as dimethylsulfoxide (DMSO). When a constitutively active ras mutant (ras12V) was expressed in SKT6 cells, EPO-induced di erentiation was inhibited. Conversely, a dominant negative ras mutant (ras17N) induced di erentiation even in the absence of EPO, suggesting that the basal Ras activity is essential for the maintenance of the undi erentiated phenotype and proliferative potential in this cell line. Rapid inactivation of ERK was observed after expression of ras17N. Slow but signi®cant inactivation of ERK was also observed during EPOinduced di erentiation. Furthermore, overexpression of a constitutively active mutant of ERK-activating kinase (MAPKK) was found to suppress erythroid di erentiation, while pharmacological inhibition of MAPKK induced di erentiation. These ®ndings suggest that down-regulation of Ras/ERK signaling pathway may be an essential event in EPO-induced erythroid di erentiation in this system. Oncogene (2000) 19, 1500 ± 1508.

show abstract

Section: Discussionmentioning

confidence: 58%

“…Conversely, forced expression of protein tyrosine phosphatase b2 gene was found to induce di erentiation in murine erythroleukemia cells (Kume et al, 1996). In addition, Jak2-de®cient mice were found to have defects in de®nitive erythropoiesis which lead to embryonic death due to anemia (Parganas et al, 1998;Neubauer et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

et al. 2000

View full text Add to dashboard Cite

show abstract

“…JAK-2 mediates signaling via the hematopoietic cytokines EPO, GM-CSF, and thrombopoietin (8,9). Patients receiving the highest dosage of CP-690,550 (30 mg twice daily) had higher incidences of anemia, granulocytopenia, and thrombocytopenia than did the placebo group (12).…”

Section: Discussionmentioning

confidence: 99%

“…Tyk-2 deficiency results in a human primary immunodeficiency similar to the JAK-3 SCID phenotype; however, neither JAK-1-deficient nor JAK-2-deficient humans have been identified, and deficient mice are not viable (8,9). Several of the cytokines that require JAK-1, JAK-2, and/or Tyk-2 activity, including IL-6, IL-12, and IL-23, play a pathogenic role in human rheumatoid arthritis (RA) (10,11), suggesting that inhibiting the JAK family more broadly may be beneficial.…”

mentioning

confidence: 99%

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Lin

Hegen

Quadros

et al. 2010

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. All ␥-chain cytokines signal through JAK-3 and JAK-1 acting in tandem. We undertook this study to determine whether the JAK-3 selective inhibitor WYE-151650 would be sufficient to disrupt cytokine signaling and to ameliorate autoimmune disease pathology without inhibiting other pathways mediated by JAK-1, JAK-2, and Tyk-2.Methods. JAK-3 kinase selective compounds were characterized by kinase assay and JAK-3-dependent (interleukin-2 [IL-2]) and -independent (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]) cell-based assays measuring proliferation or STAT phosphorylation. In vivo, off-target signaling was measured by IL-22-and erythropoietin (EPO)-mediated models, while on-target signaling was measured by IL-2-mediated signaling. Efficacy of JAK-3 inhibitors was determined using delayed-type hypersensitivity (DTH) and collagen-induced arthritis (CIA) models in mice.Results. In vitro, WYE-151650 potently suppressed IL-2-induced STAT-5 phosphorylation and cell proliferation, while exhibiting 10-29-fold less activity against JAK-3-independent IL-6-or GM-CSF-induced STAT phosphorylation. Ex vivo, WYE-151650 suppressed IL-2-induced STAT phosphorylation, but not IL-6-induced STAT phosphorylation, as measured in whole blood. In vivo, WYE-151650 inhibited JAK-3-mediated IL-2-induced interferon-␥ production and decreased the natural killer cell population in mice, while not affecting IL-22-induced serum amyloid A production or EPO-induced reticulocytosis. WYE-151650 was efficacious in mouse DTH and CIA models.Conclusion. In vitro, ex vivo, and in vivo assays demonstrate that WYE-151650 is efficacious in mouse CIA despite JAK-3 selectivity. These data question the need to broadly inhibit JAK-1-, JAK-2-, or Tyk-2-dependent cytokine pathways for efficacy.

show abstract

“…Using dominant negative JAK2, we found that JAK2 plays an essential role in activities induced by GM-CSF such as proliferation, induction of immediate early genes, phosphorylation of cellular proteins and bc itself (Watanabe et al, 1996). JAK2 knockout mice are embryonic lethal due to the absence of any de®nitive erythropoiesis (Neubauer et al, 1998;Parganas et al, 1998) and myeloid progenitors from the fetal liver of JAK2-de®cient mice failed to respond to erythropoietin, IL-3 and GM-CSF. When we analysed various bc mutants in BA/F3 and NIH3T3 cells, we found that multiple signaling pathways downstream of JAK2 are activated by hGM-CSFR (Watanabe et al, 1993(Watanabe et al, , 1995.…”

Section: Introductionmentioning

confidence: 99%

Analysis of mechanisms involved in the prevention of γ irradiation-induced apoptosis by hGM-CSF

Liu

Mohi

et al. 2000

Oncogene

View full text Add to dashboard Cite

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains viability of the mouse interleukin (IL)-3 dependent lymphoid cell line BA/F3 expressing the hGM-CSF receptor. Caspase-3 like enzyme activity and DNA fragmentation were augmented by depletion of this factor from the cell, and exposure to g irradiation accelerated kinetics of these events. Anti g irradiationinduced apoptosis occurred through various mutant GM-CSF receptors and only the box1 region was essential while the C terminal region, including tyrosine residues which are required for MAPK cascade activation, was dispensable. Consistent with this notion, the addition of PD98059 had no e ect on this activity thereby indicating that activation of MAPK is not essential for the activity. As expected, g irradiation increased p53 protein and bax mRNA levels and the presence of hGM-CSF dramatically modulated bax/bcl-X L ratio. The PI-3K speci®c inhibitor wortmannin did not a ect hGM-CSF dependent anti g irradiation induced apoptosis nor bcl-X L induction, thus bcl-X L but not PI-3K pathway seems to be involved in hGM-CSF dependent anti g irradiation-induced apoptosis. It is well documented that the box1 region is essential for GM-CSF dependent activation of JAK2 and JAK2 speci®c inhibitor AG490 suppressed anti g irradiation-induced apoptosis by hGM-CSF. An arti®cial JAK2 activating molecule in which extracellular and the transmembrane of bc fused with whole JAK2 can sustain BA/F3 cells survival and proliferation mIL-3 independently, but these cells are susceptible to g irradiation. Furthermore GyrB/Jak2, which can activate STAT5 but not the MAPK cascade nor survival of BA/F3 cells, also could not prevent g irradiation-induced apoptosis. Although JAK2 is essential for hGM-CSF dependent anti g irradiation-induced apoptosis, it appeared that JAK2 does not seem su cient for the activity. Oncogene (2000) 19, 571 ± 579.

show abstract

Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis

Cited by 762 publications

References 73 publications

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

Selective functional inhibition of JAK‐3 is sufficient for efficacy in collagen‐induced arthritis in mice

Analysis of mechanisms involved in the prevention of γ irradiation-induced apoptosis by hGM-CSF

Contact Info

Product

Resources

About