Characterization of the chronic myelomonocytic leukemia associated TEL-PDGFβR fusion protein

Sjöblom, Tobias; Boureux, Anthony; Rönnstrand, Lars; Heldin, Carl‐Henrik; Ghysdael, Jacques; Östman, Arne

doi:10.1038/sj.onc.1203190

Cited by 35 publications

(34 citation statements)

References 32 publications

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“…[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]34 WT1 is expressed in a variety of tissues including ovary, testis and spleen. In normal BM, WT1 expression is low and even lower in normal PB where in a percentage of cases, it is undetectable even by RT-PCR and RQ-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…Many of these abnormalities such as t(2;4) (p24;q12), 29 30 the deletion of chromosome Y 31 and t(5;12) (q33;p13). 32 For other cytogenetic abnormalities, there is no evidence of a direct relationship with the development of hypereosinophilia, we can consider the presence of a clonality marker and the absence of any other hematopoietic disorders associated with eosinophilia as suggestive for the Figure 1). CEL patients showed a mean number of WT1 copies/ 10 4 ABL copies of 6117667 (median ¼ 440, range 77-633) in BM and 1487125 (median ¼ 108, range 20-679) in PB.…”

Section: Cytogenetic and Molecular Analysismentioning

confidence: 99%

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WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia

et al. 2007

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Idiopathic hypereosinophilic syndromes (HES) comprise a spectrum of indolent to aggressive diseases characterized by persistent hypereosinophilia. Hypereosinophilia can result from the presence of a defect in the hematopoietic stem cell giving rise to eosinophilia, it can be present in many myeloproliferative disorders or alternatively it may be a reactive form, secondary to many clinical conditions. The hybrid gene FIP1L1-PDGRFa was identified in a subset of patients presenting with HES or chronic eosinophilic leukemia (CEL). In spite of this, the majority of HES patients do not present detectable molecular lesions and for many of them the diagnosis is based on exclusion criteria and sometimes it remains doubt. In this study we explored the possibility to distinguish between HES/ CEL and reactive hypereosinophilia based on WT1 transcript amount. For this purpose, 312 patients with hypereosinophilia were characterized at the molecular and cytogenetic level and analyzed for WT1 expression at diagnosis and during follow-up. This study clearly demonstrates that WT1 quantitative assessment allows to discriminate between HES/CEL and reactive eosinophilia and represents a useful tool for disease monitoring especially in the patients lacking a marker of clonality.

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Section: Discussionmentioning

confidence: 99%

Section: Cytogenetic and Molecular Analysismentioning

confidence: 99%

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia

et al. 2007

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“…In the case of the rare disease chronic monomyelocytic leukemia (CMML), the part of the -receptor gene that encodes the kinase domain is fused to certain genes, e.g. the Tel gene, that have in common that they encode proteins that can dimerize (23)(24)(25). This results in constitutively dimerized and activated receptors, which drive tumor cell proliferation and survival.…”

Section: Pdgf In Diseasementioning

confidence: 99%

Development and possible clinical use of antagonists for PDGF and TGF-β

Heldin¹

2004

Upsala Journal of Medical Sciences

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“…For example, TelPDGRb and PDGFRb signal differently 16 and Hip-PDGFRb transforms through different pathways than native PDGFRb. 17 Here, we show that F/PDGFRa has a modulated signaling capacity compared to PDGFRa: On one hand, F/PDGFRa has a selective defect for activation of the PI3/Akt-pathway which is localization dependent.…”

Section: Introductionmentioning

confidence: 99%

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

et al. 2015

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ABSTRACT. Aberrant activation of oncogenic kinases is frequently observed in human cancers, but the underlying mechanism and resulting effects on global signaling are incompletely understood. Here, we demonstrate that the oncogenic FIP1L1-PDGFRa kinase exhibits a significantly different signaling pattern compared to its PDGFRa wild type counterpart. Interestingly, the activation of primarily membrane-based signal transduction processes (such as PI3-kinase-and MAP-kinase-pathways) is remarkably shifted toward a prominent activation of STAT factors. This diverging signaling pattern compared to classical PDGF-receptor signaling is partially coupled to the aberrant cytoplasmic localization of the oncogene, since membrane targeting of FIP1L1-PDGFRa restores activation of MAPK-and PI3K-pathways. In stark contrast to the classical cytokine-induced STAT activation process, STAT activation by FIP1L1-PDGFRa does neither require Janus kinase activity nor Src kinase activity. Furthermore, we investigated the mechanism of STAT5 activation via FIP1L1-PDGFRa in more detail and found that STAT5 activation does not involve an SH2-domain-mediated binding mechanism. We thus demonstrate that STAT5 activation occurs via a non-canonical activation mechanism in which STAT5 may be subject to a direct phosphorylation by FIP1L1-PDGFRa.

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Characterization of the chronic myelomonocytic leukemia associated TEL-PDGFβR fusion protein

Cited by 35 publications

References 32 publications

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia

WT1 transcript amount discriminates secondary or reactive eosinophilia from idiopathic hypereosinophilic syndrome or chronic eosinophilic leukemia

Development and possible clinical use of antagonists for PDGF and TGF-β

The oncogenic FIP1L1-PDGFRαfusion protein displays skewed signaling properties compared to its wild-type PDGFRαcounterpart

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