Stat5 activation enables erythropoiesis in the absence of EpoR and Jak2

Grebien, Florian; Kerényi, Marc; Kovacic, Boris; Kolbe, Thomas; Becker, Verena; Dolznig, Helmut; Pfeffer, Klaus; Klingmüller, Ursula; Müller, Mathias; Beug, Hartmut; Müllner, Ernst W.; Moriggl, Richard

doi:10.1182/blood-2007-07-102848

Cited by 95 publications

(96 citation statements)

References 63 publications

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“…39 Cells were selected with puromycin (1 g/mL) and then cloned by limiting dilution. Expression of STAT5 S710F in the presence of doxycycline (1 g/mL) was analyzed by immunoblotting.…”

Section: Generation Of Ba/f3 Cells With Conditional Expression Of Stamentioning

confidence: 99%

Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

Hoermann

Cerny-Reiterer

Perné

et al. 2011

The American Journal of Pathology

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Systemic mastocytosis is a neoplastic disease of mast cells harboring the activating KIT mutation D816V. In most patients, mast cell infiltration in the bone marrow is accompanied by marked microenvironment alterations, including increased angiogenesis, osteosclerosis, and sometimes fibrosis. Little is known about the mast cell-derived molecules contributing to these bone marrow alterations. We show here that neoplastic mast cells in patients with systemic mastocytosis express oncostatin M (OSM), a profibrogenic and angiogenic modulator. To study the regulation of OSM expression, KIT D816V was inducibly expressed in Ba/F3 cells and was found to up-regulate OSM mRNA and protein levels, suggesting that OSM is a KIT D816V-dependent mediator. Correspondingly, KIT D816V ؉ HMC-1.

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“…39 Cells were selected with puromycin (1 g/mL) and then cloned by limiting dilution. Expression of STAT5 S710F in the presence of doxycycline (1 g/mL) was analyzed by immunoblotting.…”

Section: Generation Of Ba/f3 Cells With Conditional Expression Of Stamentioning

confidence: 99%

Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

Hoermann

Cerny-Reiterer

Perné

et al. 2011

The American Journal of Pathology

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“…We used methyl-CpG immunoprecipitation followed by next-generation sequencing as described earlier. 5,53 In brief, 3 μg of genomic DNA were sonicated in a Covaris S sonicator (Covaris Inc., Woburn, MA, USA). DNA fragments, which were about 150 bp in size, were then subjected to enrichment with 60 μg MBD2-Fc protein in the presence of a sodium chloride gradient (fraction A: 300 mM; B: 400 mM; C: 500 mM; D: 550 mM; E: 1,000 mM).…”

Section: Methodsmentioning

confidence: 99%

“…For this procedure, we used a SX-8G IP-Star robot (Diagenode, Liege, Belgium) using a standard protocol as described elsewhere. 5 Desalting of eluates was performed using MinElute columns (Qiagen). Enrichment efficiency of methylated DNA was checked by qPCR using primers for the imprinted gene Mest.…”

Section: Methodsmentioning

confidence: 99%

“…This is primarily due to increased apoptosis of Stat5a and 5b-deficient erythroid progenitors. 5,6 Adult Stat5a − / − 5b − / − mice partially (30-50%) show equal numbers of red cells, hemoglobin levels and hematocrit as wild-type controls. However, anemic adult STAT5 knockout mice revealed an increase in early erythroblast numbers, which fail to differentiate.…”

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confidence: 99%

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Epo-induced erythroid maturation is dependent on Plcγ1 signaling

et al. 2014

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Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells (HSCs) into more committed progenitors and finally into erythrocytes. Binding of erythropoietin (Epo) to its receptor (EpoR) is required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Janus kinase 2 (Jak2) tyrosine kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR-Jak2 independently of Stat5. Plcγ1-deficient pro-erythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined HSCs (Lin − Sca1 + KIT + CD48 − CD150 + ) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation, we assessed changes occurring at the global transcriptional and DNA methylation level after inactivation of Plcγ1. The top common downstream effector was H2afy2, which encodes for the histone variant macroH2A2 (mH2A2). Inactivation of mH2A2 expression recapitulated the effects of Plcγ1 depletion on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target mH2A2, as a 'non-canonical' Epo signaling pathway essential for erythroid differentiation.

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“…96 In JAK2À/À fetal mouse livers, constitutive expression of a STAT5a mutant rescues the defect in HSC maintenance. 97 These experiments have provided the impetus for examining whether or not JAK2 plays a role in human stem cell maintenance. Because of increased availability of more highly immunocompromised mice together with advances in lentiviral technology and non-invasive in vivo imaging, this can now be tested in xenogeneic transplantation models with JAK2-lentivirally transduced human HSC and embryonic stem (hES) cells to determine developmental stage at which stem cells are most susceptible to instructive cues from JAK2.…”

Section: Bcr-abl-negative Mpd Stem and Progenitor Cell Self-renewalmentioning

confidence: 99%