|Year : 2015 | Volume
| Issue : 1 | Page : 31-34
Phosphoinositide 3-kinase/Akt Pathway Mediates Fip1-like1-platelet-derived Growth Factor Receptor α-induced Cell Infiltration and Activation: Possible Molecular Mechanism for the Malignant Phenotype of Chronic Eosinophilic Leukemia
Bin Li1, Guangsen Zhang2, Ruijuan Li2, Chaojun Duan3
1 Division of Oncology; Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
2 Division of Hematology, Institute of Molecular Hematology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
3 Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China
|Date of Submission||06-Jan-2015|
|Date of Acceptance||04-Feb-2015|
|Date of Web Publication||16-Feb-2015|
Prof. Chaojun Duan
Institute of Medical Sciences, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan
Source of Support: This work was supported by grants from the Natural Scientific Foundation of China (81200366,81171841) and Province Natural Scientific Foundation of Hunan (No. 14JJ6004) and the Key Subject Education Department of Hunan (594),, Conflict of Interest: None
The fip1-like1/platelet-derived growth factor receptor-α fusion gene (F/P) is responsible for 14-60% cases of hypereosinophilia syndrome (HES), also known as F/P-positive chronic eosinophilic leukemia (F/P(+) CEL). The major pathogenesis of F/P(+) CEL is known to involve migration and activation of mast cells and eosinophils, leading to severe multi-organ dysfunction, but the mechanism was still unclear. Phosphoinositide 3-kinase (PI3K) and serine-threonine protein kinase Akt have been reported to be targets of F/P in the F/P-promoted cell proliferation. They are extensively involved in the migration and adhesion of hematopoietic stem/progenitor cells, and also control cell invasion in some leukemias. The PI3K/Akt pathway is involved in eosinophil/neutrophil activation and infiltration; its possible role in regulating F/P induced cytotoxicity and upregulation of A4-integrin in eosinophils, and inducing eosinophil activation through controlling F/P-induced Nuclear factor-kB activity. Akt was recently shown to be stimulated by F/P, synergistically with stem cell factor, resulting in the induction of MCs migration and excessive activation. PI3K/Akt pathway is also a principal mediator of interleukin-5 (IL-5)-induced signal transduction promoting eosinophil trafficking and degranulation, whereas IL-5 is a necessary cytokine for F/P-mediated CEL development. We, therefore, propose the hypothesis that the PI3K/Akt pathway might be vital downstream of F/P to induce target cell activation and tissue infiltration, resulting in the malignant phenotype seen in F/P(+) CEL.
Keywords: Fip1-like1-platelet-derived growth factor receptor-α, malignant phenotype, phosphoinositide 3-kinase/Akt pathway
|How to cite this article:|
Li B, Zhang G, Li R, Duan C. Phosphoinositide 3-kinase/Akt Pathway Mediates Fip1-like1-platelet-derived Growth Factor Receptor α-induced Cell Infiltration and Activation: Possible Molecular Mechanism for the Malignant Phenotype of Chronic Eosinophilic Leukemia. Cancer Transl Med 2015;1:31-4
|How to cite this URL:|
Li B, Zhang G, Li R, Duan C. Phosphoinositide 3-kinase/Akt Pathway Mediates Fip1-like1-platelet-derived Growth Factor Receptor α-induced Cell Infiltration and Activation: Possible Molecular Mechanism for the Malignant Phenotype of Chronic Eosinophilic Leukemia. Cancer Transl Med [serial online] 2015 [cited 2019 Dec 11];1:31-4. Available from: http://www.cancertm.com/text.asp?2015/1/1/31/151490
| Introduction|| |
An interstitial deletion on chromosome 4q12 results in the formation of the fip1-like1/platelet-derived growth factor receptor-α fusion gene (F/P). The fusion gene product acts as a constitutively active tyrosine kinase, triggering the development of chronic eosinophilic leukemia (CEL).  The predominant clinical and pathologic features are severe multi-organ dysfunction as a result of eosinophilic infiltration and cytotoxicity, with cardiovascular system damage being a major cause of death in F/P-induced CEL, compared to F/P-negative hypereosinophilic syndrome (HES). , Systemic mastocytosis (SM) with infiltration of nonhematopoietic tissues represents another common clinical manifestation in F/P(+) CEL.  Recent experiments in a murine model of F/P(+) CEL showed that F/P induced mast cell (MC) migration and extensive infiltration, in synergism with striking eosinophil invasion in the involved organs.  However, the underlying molecular mechanisms remain poorly understood.
| Fip1-Like1/Platelet-Derived Growth Factor Receptor-α-Induced Malignant Phenotype of Chronic Eosinophilic Leukemia|| |
The F/P fusion gene is responsible for 14-60% of cases of HES. These patients are classified as F/P(+) CEL.  Clinically, F/P(+) CEL is often accompanied by SM, and up to half of SM with hypereosinophilia (SM-Eo) patients carry the F/P fusion gene (F/P(+) CEL/SM).  These overlapping phenotypes were also observed in the F/P-induced murine model. ,, Compared to F/P(−) HES or SM, F/P(+) CEL/SM patients appear to have a more severe disease phenotype involving extensive end-organ pathology.  These patients often develop cardiac and pulmonary symptoms, and abnormalities of the cardiovascular system are the primary cause of morbidity and mortality. Eosinophil cytotoxicity and tissue fibrosis have been demonstrated histopathologically in the involved organs in F/P(+) CEL/SM. ,, Upregulation of A4-integrin and Siglec-F expression in the F/P-transfected cells, associated with eosinophil adhesion and migration, is an important indication of F/P-induced eosinophil activation.  In addition, F/P can promote MCs migration and induce increased MCs infiltration into multiple organs in F/P(+) CEL mice compared to F/P(−) control mice in response to stem cell factor (SCF).  Serum levels of activated mast-cell tryptase were elevated in F/P(+) CEL, associated with tissue fibrosis and poor prognosis.  These results suggest a relationship between F/P-induced target cell activation and malignant phenotype in CEL.
In both in vitro and in vivo experiments, mice transplanted with CD2- interleukin-5 (IL-5)-transgenic F/P(+) hematopoietic stem/progenitor cells (HSC/Ps) (IL-5Tg-F/P recipients) showed higher eosinophil contents in the myocardium and lung, and significant eosinophilia in the peripheral blood and bone marrow. In contrast, mock-vector-transduced CD2-IL-5-transplanted mice (IL-5Tg-mock vector recipients) developed blood, but not tissue eosinophilia, as seen in F/P(+) CEL. Intriguingly, mice transplanted with nontransgenic F/P-transduced HSC/Ps (non-Tg-F/P recipients) showed obvious tissue granulocyte infiltration.  These different phenotypes were attributed to the capability of the F/P gene to induce target cell activation and tissue infiltration. Some experts proposed that F/P could enhance SCF-or IL-5-stimulated intracellular signaling leading to the CEL phenotype. , PKC-delta is a critical mediator of IL-5, cooperating with the chemokine to induce eosinophil migration in most allergic diseases, but it was not the downstream of F/P gene and also unrelated with the activated phosphoinositide 3-kinase (PI3K) signal pathway in the F/P(+) chronic eosinophilic leukemia cell (EoL-1 cell). ,, It is, therefore, important to investigate which intracellular signaling pathway is responsible for mediating the F/P-induced cell invasion phenotype, and to determine if these molecules are shared downstream of F/P with IL-5/SCF.
| Phosphoinositide 3-Kinase/Akt and Cell Migration/Activation|| |
The PI3K/Akt pathway is a vital transduction cascade involved in many essential cellular activities, including Ras-stimulated migration and invasion of tumor cells.  The PI3K/Akt signaling module plays a critical role in regulating the migration and adhesion of HSC/Ps,  and in controlling cell migration and invasion associated with the progression of many hematological malignancies.  Moreover, the PI3K/Akt pathway is a principal mediator of IL-5-induced signal transduction to promote eosinophil trafficking and degranulation.  Akt kinase is also crucial for the SCF/c-kit receptor-dependent pathway involved in MCs migration and activation. 
| Hypothesis|| |
The above findings suggest that PI3K/Akt kinase may mediate F/P-induced target cell infiltration and activation in the CEL. In the F/P-induced CEL/SM murine model, the activation of Akt, but not that of Stat5 or ERK, is the mediator of F/P gene cooperating with SCF to induce MCs migration and infiltration.  This hypothesis is also based on the following evidence. Firstly, PI3K and Akt kinase are both activated by F/P resulting in cytokine-independent colony formation, which indicates that PI3K/Akt signal pathway is the downstream of F/P gene in the CEL. , Secondly, PI3K kinase participates in eosinophil migration and degranulation stimulated by different chemotaxins, and critically regulates the recruitment and survival of eosinophils in vivo through activation of Akt. , Recently, enhanced chemotactic factor-induced Akt phosphorylation was observed in IL-5-primed eosinophils.  Interestingly, non-Tg-F/P recipient mice showed a chronic myeloid leukemia phenotype with obvious tissue neutrophil infiltration.  The PI3K/Akt signaling cascade is also involved in migration, degranulation, superoxide production and survival in neutrophils. , These results present compelling evidence to implicate the PI3K/Akt pathway as a possible mediator of F/P-induced target cell invasion phenotype. Thirdly, F/P was reported to produce intracellular reactive oxygen species (ROS) by activation of NADPH oxidase in a PI3K-dependent manner.  In addition, IL-5 converged on the PI3K signaling pathway to regulate NADPH oxidase activity in human eosinophils, while Los et al. reported that Akt increased ROS and suppressed antioxidant enzymes.  These results suggest that PI3K/Akt kinase may be the pathway whereby F/P facilitates IL-5-stimulated intracellular signaling leading to eosinophil cytotoxicity. Fourthly, our preliminary study recently revealed that PI3K/AKT signaling play a key role in the JAK2-mediated F/P-positive eosinophil infiltration and degranulation.  Nuclear factor (NF)-κB lies downstream of the PI3K/AKT pathway in F/P signal cascade, which also plays a key role in the recruitment and activation of EoL-1 cells. , These findings indicate that the PI3K/Akt signal may induce eosinophil activation through controlling F/P-induced NF-κB activity. Finally, up-regulation of A4-integrin expression related to eosinophil migration was detected in a case of CEL and in the murine model of IL-5-Tg-F/P recipients.  Akt kinase induced overexpression of the A4-integrin in melanoma cells and in childhood B-cell precursor acute lymphoblastic leukemia with highly invasive cell phenotype, , suggesting that Akt may be a vital mediator regulating F/P-induced upregulation of A4-integrin in eosinophils.
| Discussion|| |
Accumulated evidence suggests that PI3K/Akt kinase may act downstream of F/P to increase the invasiveness of target cells, including eosinophils, neutrophils, and MCs. These activated target cells induced by the F/P gene interact with each other, resulting in synergistic end-organ injury. Targeting the PI3K/Akt signal may thus represent an effective and feasible method for inhibiting F/P-associated tissue infiltration and dysfunction. Further research is needed to validate this hypothesis. The hypothesis is outlined schematically in [Figure 1].
|Figure 1: Phosphoinositide 3-kinase/Akt pathway mediates fip1-like1-platelet-derived growth factor receptor-α -induced cell infiltration and activation|
Click here to view
| Acknowledgments|| |
This work was supported by grants from the Natural Scientific Foundation of China (81200366,81171841) and Province Natural Scientific Foundation of Hunan (No. 14JJ6004) and the Key Subject Education Department of Hunan ((2012)594).
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