Tel/PDGFRβ induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways

Dobbin, Edwina; Graham, Ciaren; Corrigan, Pamela M.; Thomas, Keith; Freeburn, Robin W.; Wheadon, Helen

doi:10.1016/j.exphem.2008.09.012

Cited by 12 publications

(11 citation statements)

References 40 publications

(70 reference statements)

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“…In the leukemic model, the transforming TP oncoprotein self-associates and activates kinase-dependent signaling pathways [48]. Previous studies demonstrate that TP inhibits ES self-renewal and promotes myeloid differentiation [24,49]. This phenotype was validated by reduction in alkaline phosphatase expression and upregulation of Hoxb4 and Cdx4.…”

Section: Transcriptional Flux Of Hox Network In Es Cell Modelsdiscussionmentioning

confidence: 90%

“…This phenotype was validated by reduction in alkaline phosphatase expression and upregulation of Hoxb4 and Cdx4. Increased Hoxb4 and Cdx4 expression levels are known to enhance the clonogenic potential of EB-derived cells during hematopoietic differentiation [49,50]. Recent evidence suggests that Cdx4 is upregulated in 23% of AML patients, with preferential expression shown in primitive stem and progenitor cells.…”

Section: Transcriptional Flux Of Hox Network In Es Cell Modelsdiscussionmentioning

confidence: 99%

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DifferentialHoxExpression in Murine Embryonic Stem Cell Models of Normal and Malignant Hematopoiesis

Wheadon

Ramsey

Dobbin

et al. 2011

Stem Cells and Development

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Section: Transcriptional Flux Of Hox Network In Es Cell Modelsdiscussionmentioning

confidence: 90%

Section: Transcriptional Flux Of Hox Network In Es Cell Modelsdiscussionmentioning

confidence: 99%

DifferentialHoxExpression in Murine Embryonic Stem Cell Models of Normal and Malignant Hematopoiesis

Wheadon

Ramsey

Dobbin

et al. 2011

Stem Cells and Development

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“…To compare the signaling properties of the two proteins, we performed intracellular staining of phospho-STAT5 and phospho-ERK1/2 (Fig. 4B), which are two important signaling mediators of TP␤ (19,20,23). As expected, TP␤ induced the phosphorylation of both proteins in Ba/F3 cells.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, TP␤ is not efficiently degraded in cells, and we showed that its increased stability promotes cell proliferation (22). Recently, activation of ERK signaling proteins was indicated as a mediator of TP␤-induced stem cell differentiation (23).…”

Section: Pdgfr␤mentioning

confidence: 99%

Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) β Transmembrane Domain in the TEL-PDGFRβ Cytosolic Oncoprotein

Toffalini

Hellberg

Demoulin

2010

Journal of Biological Chemistry

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The fusion of TEL with platelet-derived growth factor receptor (PDGFR) ␤ (TP␤) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TP␤ is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFR␤ kinase domain. The receptor transmembrane (TM) domain is retained in TP␤ and in most of the described PDGFR␤ hybrids. Deletion of the TM domain (⌬TM-TP␤) strongly impaired the ability of TP␤ to sustain growth factor-independent cell proliferation. We confirmed that TP␤ resides in the cytosol, indicating that the PDGFR␤ TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The ⌬TM-TP␤ protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TP␤. In an in vitro kinase assay, ⌬TM-TP␤ was more active than TP␤ and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TP␤-mediated signaling and proliferation, suggesting that the activation of the PDGFR␤ kinase domain is not enough for cell transformation.

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“…The presence of JAK3 changes in healthy individuals may identify a novel risk group. The constitutive activation of JAK/STAT pathways has been frequently documented in chronic myeloid proliferative disorders as result of the expression of novel chimeric proteins [23,24], which contribute to the cellular transformation [25] and to maintenance of the neoplastic phenotype [26,27]. In this context, the oncogenic role of JAK3 was suggested by its frequent expression and/or activation in several cancers even in the absence of known mutations [28] and by its co-association with activated STATs.…”

Section: Discussionmentioning

confidence: 99%

Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects

Riera¹,

Lasorsa²,

Bonello³

et al. 2011

Leukemia & Lymphoma

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Gain-of-function (GOF) mutations of Janus kinase 2 (JAK2) are frequently seen in myeloproliferative disorders (MPDs). Meanwhile, JAK3 activating substitutions have been found in a few megakaryocytic cell lines and in primary myeloid leukemia (AMKL). Here, we sought to discover novel leukemogenetic mutations in de novo acute myeloid leukemia of non-Down syndrome (N-DS) by DNA sequencing. A total of 191 normal Caucasian individuals were studied to define single nucleotide polymorphisms (SNPs) within the JH2 and JH6 domains. Although known activating substitutions were observed in rare cases of acute myeloid leukemia (AML) (V722I [2/134] or P132T [1/119]), all samples were wild-type (WT) for the oncogenic A572V (119/119). Interestingly, a novel homozygous mutation (P132A) was discovered in a patient with acute megakaryoblastic leukemia and in vivo studies demonstrated that its ectopic expression was oncogenic in a mouse xenotransplant model. This study defines a novel JAK3 mutation among patients with N-DS AML and demonstrates that normal individuals can also display germline JAK3 substitutions, previously proven to have oncogenic properties, in vitro and in vivo. The discovery of these substitutions in normal donors encourages future studies to define new risk factors among patients with MPDs.

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Tel/PDGFRβ induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways

Cited by 12 publications

References 40 publications

DifferentialHoxExpression in Murine Embryonic Stem Cell Models of Normal and Malignant Hematopoiesis

DifferentialHoxExpression in Murine Embryonic Stem Cell Models of Normal and Malignant Hematopoiesis

Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) β Transmembrane Domain in the TEL-PDGFRβ Cytosolic Oncoprotein

Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects

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