Mechanisms for the proliferation of eosinophilic leukemia cells by FIP1L1-PDGFRα

Ishihara, Kenji; Kitamura, Hajime; Hiraizumi, Kenji; Kaneko, Motoko; Takahashi, Aki; Zee, Ok Pyo; Seyama, Toshio; Hong, Jang Ja; Ohuchi, Kazuo; Hirasawa, Noriyasu

doi:10.1016/j.bbrc.2007.12.063

Cited by 8 publications

(10 citation statements)

References 16 publications

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“…1 A later study identified STAT5/ERK/JNK as activated signaling components downstream of the F/ PDGFRa, in contrast to p38 MAPK and AKT that were found to be activated by other, unknown mechanisms. 34 Opposing data from another group identified p38 MAPK and AKT to be activated when the F/PDGFRa was retrovirally transduced. 41 With regard to these conflicting results, we decided to perform a comparative analysis of F/PDGFRa and PDGFRa-wt under more standardized conditions, including the effects of the membrane re-localization of F/PDGFRa on its signaling behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, this described recruitment site is located in the juxtamembrane region of the PDGFRa-wt and is missing in the F/PDGFRa fusion protein, although STAT5 phosphorylation was reported. 1,34 To study the details of STAT5 activation, we therefore generated a series of tyrosine to phenylalanine mutations in our oncogenic PDGFRa proteins (Fig. 5A).…”

Section: Activation Of Stat5 Does Not Require An Sh2-mediated Recruitmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Activation Of Stat5 Does Not Require An Sh2-mediated Recruitmentioning

confidence: 99%

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

et al. 2015

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“…F/P(+) CEL is characterized by hyperproliferation of clonal eosinophils and life-threatening organ damage, especially affecting the lungs and/or the heart, due to eosinophil degranulation of toxic mediators [2]. The F/P fusion protein acts as a constitutive activator of the transmembrane receptor protein-PDGFRA [3], [4], which activates several signal molecules such as PI3K, MEK, JNK, ERK1/2 and the Stats [5], [6], [7]. However, to date, it remains largely unknown which intracellular activated pathways and critical signal molecules underlie the F/P-mediated malignant phenotype of CEL.…”

Section: Introductionmentioning

confidence: 99%

“…F/P induction of c-Myc promotes EOL-1 cellular proliferation, and the anti-apoptosis activity of F/P in eosinophils may be associated with high expression levels of cellular Survivin [7], [12]. Nonetheless, the mechanism by which F/P regulates c-Myc and Survivin is unknown.…”

Section: Introductionmentioning

confidence: 99%

Identification of JAK2 as a Mediator of FIP1L1-PDGFRA-Induced Eosinophil Growth and Function in CEL

Zhang

et al. 2012

PLoS ONE

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The Fip1-like1 (FIP1L1)-platelet-derived growth factor receptor alpha fusion gene (F/P) arising in the pluripotent hematopoietic stem cell (HSC),causes 14% to 60% of patients with hypereosinophilia syndrome (HES). These patients, classified as having F/P (+) chronic eosinophilic leukemia (CEL), present with clonal eosinophilia and display a more aggressive disease phenotype than patients with F/P (–) HES patients. The mechanisms underlying predominant eosinophil lineage targeting and the cytotoxicity of eosinophils in this leukemia remain unclear. Given that the Janus tyrosine kinase (JAK)/signal transducers and activators of transcription (Stat) signaling pathway is key to cytokine receptor-mediated eosinophil development and activated Stat3 and Stat5 regulate the expression of genes involved in F/P malignant transformation, we investigated whether and how JAK proteins were involved in the pathogenesis of F/P-induced CEL. F/P activation of JAK2, Stat3 and Stat5, were confirmed in all the 11 F/P (+) CEL patients examined. In vitro inhibition of JAK2 in EOL-1, primary F/P(+) CEL cells (PC) and T674I F/P Imatinib resistant cells(IR) by either JAK2-specific short interfering RNA (siRNA) or the tryphostin derivative AG490(AG490), significantly reduced cellular proliferation and induced cellular apoptosis. The F/P can enhance the IL-5-induced JAK2 activation, and further results indicated that JAK2 inhibition blocked IL-5-induced cellular migration and activation of the EOL-1 and PC cells in vitro. F/P-stimulation of the JAK2 suppressed cells led to a significantly reduction in Stat3 activation, but relatively normal induction of Stat5 activation. Interestingly, JAK2 inhibition also reduced PI3K, Akt and NF-κB activity in a dose-dependent manner, and suppressed expression levels of c-Myc and Survivin. These results strongly suggest that JAK2 is activated by F/P and is required for F/P stimulation of cellular proliferation and infiltration, possibly through induction of c-Myc and Survivin expression via activation of multiple signaling pathways, including NF-κB, Stat3, and PI3K/Akt.

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“…Neoplastic eosinophils in CEL display PDGFRA fusion genes in most cases [3], [4], [5], [6]. Most common are FIP1L1-PDGFRA (F/P) fusions on 4q12, resulting in F/P + leukaemia [3], [5], [6].…”

Section: Introductionmentioning

confidence: 99%

Nilotinib and Imatinib Are Comparably Effective in Reducing Growth of Human Eosinophil Leukemia Cells in a Newly Established Xenograft Model

et al. 2012

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We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL) to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL.

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Mechanisms for the proliferation of eosinophilic leukemia cells by FIP1L1-PDGFRα

Cited by 8 publications

References 16 publications

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

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

Identification of JAK2 as a Mediator of FIP1L1-PDGFRA-Induced Eosinophil Growth and Function in CEL

Nilotinib and Imatinib Are Comparably Effective in Reducing Growth of Human Eosinophil Leukemia Cells in a Newly Established Xenograft Model

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