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HYPOTHESIS
Year : 2015  |  Volume : 1  |  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


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 Submission06-Jan-2015
Date of Acceptance04-Feb-2015
Date of Web Publication16-Feb-2015

Correspondence Address:
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
China
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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 ([2012]594),, Conflict of Interest: None


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  Abstract 

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 Top


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). [1] 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). [2],[3] Systemic mastocytosis (SM) with infiltration of nonhematopoietic tissues represents another common clinical manifestation in F/P(+) CEL. [4] 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. [5] However, the underlying molecular mechanisms remain poorly understood.


  Fip1-Like1/Platelet-Derived Growth Factor Receptor-α-Induced Malignant Phenotype of Chronic Eosinophilic Leukemia Top


The F/P fusion gene is responsible for 14-60% of cases of HES. These patients are classified as F/P(+) CEL. [6] 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). [7] These overlapping phenotypes were also observed in the F/P-induced murine model. [7],[8],[9] 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. [3] 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. [7],[10],[11] 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. [5] 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). [8] Serum levels of activated mast-cell tryptase were elevated in F/P(+) CEL, associated with tissue fibrosis and poor prognosis. [7] 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. [5] 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. [12],[13] 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). [14],[15],[16] 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 Top


The PI3K/Akt pathway is a vital transduction cascade involved in many essential cellular activities, including Ras-stimulated migration and invasion of tumor cells. [17] The PI3K/Akt signaling module plays a critical role in regulating the migration and adhesion of HSC/Ps, [18] and in controlling cell migration and invasion associated with the progression of many hematological malignancies. [19] Moreover, the PI3K/Akt pathway is a principal mediator of IL-5-induced signal transduction to promote eosinophil trafficking and degranulation. [20] Akt kinase is also crucial for the SCF/c-kit receptor-dependent pathway involved in MCs migration and activation. [8]


  Hypothesis Top


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. [8] 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. [6],[21] 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. [22],[23] Recently, enhanced chemotactic factor-induced Akt phosphorylation was observed in IL-5-primed eosinophils. [20] Interestingly, non-Tg-F/P recipient mice showed a chronic myeloid leukemia phenotype with obvious tissue neutrophil infiltration. [5] The PI3K/Akt signaling cascade is also involved in migration, degranulation, superoxide production and survival in neutrophils. [24],[25] 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. [26] 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. [27] 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. [28] 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. [29],[30] 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. [5] 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, [26],[31] suggesting that Akt may be a vital mediator regulating F/P-induced upregulation of A4-integrin in eosinophils.


  Discussion Top


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 Top


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).

 
  References Top

1.
Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348(13): 1201 -0 14.  Back to cited text no. 1
    
2.
Helbig G, Moskwa A, Hus M, Piszcz J, Swiderska A, Urbanowicz A, Calbecka M, Gajkowska J, Seferynska I, Halasz M, Woszczyk D, Markiewicz M, Krzemien S. Clinical characteristics of patients with chronic eosinophilic leukaemia (CEL) harbouring FIP1L1-PDGFRA fusion transcript-results of Polish multicentre study. Hematol Oncol 2010; 28(2): 93-7.  Back to cited text no. 2
    
3.
Vandenberghe P, Wlodarska I, Michaux L, Zachee P, Boogaerts M, Vanstraelen D, Herregods MC, Van Hoof A, Selleslag D, Roufosse F, Maerevoet M, Verhoef G, Cools J, Gilliland DG, Hagemeijer A, Marynen P. Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. Leukemia 2004; 18(4): 734-42.  Back to cited text no. 3
    
4.
Yamada Y, Cancelas JA, Rothenberg ME. Murine model of hypereosinophilic syndromes/chronic eosinophilic leukemia. Int Arch Allergy Immunol 2009; 149(Suppl 1): 102-7.  Back to cited text no. 4
    
5.
Yamada Y, Rothenberg ME, Lee AW, Akei HS, Brandt EB, Williams DA, Cancelas JA. The FIP1L1-PDGFRA fusion gene cooperates with IL-5 to induce murine hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL)-like disease. Blood 2006; 107(10): 4071-9.  Back to cited text no. 5
    
6.
Buitenhuis M, Verhagen LP, Cools J, Coffer PJ. Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation. Cancer Res 2007; 67(8): 3759-66.  Back to cited text no. 6
    
7.
Klion AD, Noel P, Akin C, Law MA, Gilliland DG, Cools J, Metcalfe DD, Nutman TB. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood 2003; 101(12): 4660-6.  Back to cited text no. 7
    
8.
Yamada Y, Sanchez-Aguilera A, Brandt EB, McBride M, Al-Moamen NJ, Finkelman FD, Williams DA, Cancelas JA, Rothenberg ME. FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome. Blood 2008; 112(6): 2500-7.  Back to cited text no. 8
    
9.
Patnaik MM, Rindos M, Kouides PA, Tefferi A, Pardanani A. Systemic mastocytosis: a concise clinical and laboratory review. Arch Pathol Lab Med 2007; 131(5): 784-91.  Back to cited text no. 9
    
10.
Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M, Metcalfe DD, Dunbar C, Nutman TB. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 2004; 103(2): 473-8.  Back to cited text no. 10
    
11.
Kahn JE, Dutoit-Lefevre V, Duban-Deweer S, Chafey P, Pottiez G, Lefranc D, Fain O, Cordier JF, Hatron PY, Bletry O, Prin L. Comparative proteomic analysis of blood eosinophils reveals redox signaling modifications in patients with FIP1L1-PDGFRA-associated chronic eosinophilic leukemia. J Proteome Res 2011; 10(4): 1468-80.  Back to cited text no. 11
    
12.
Yamada Y, Cancelas JA. FIP1L1/PDGFR alpha-associated systemic mastocytosis. Int Arch Allergy Immunol 2010; 152(Suppl 1): 101-5.  Back to cited text no. 12
    
13.
Cools J. FIP1L1/PDGFRalpha's Kit to stimulate mast cells. Blood 2008; 112(6): 2179.  Back to cited text no. 13
    
14.
Langlois A, Chouinard F, Flamand N, Ferland C, Rola-Pleszczynski M, Laviolette M. Crucial implication of protein kinase C (PKC)-delta, PKC-zeta, ERK-1/2, and p38 MAPK in migration of human asthmatic eosinophils. J Leukoc Biol 2009; 85(4): 656-63.  Back to cited text no. 14
    
15.
Lee JS, Kim IS. Leukotactin-1/CCL15 induces cell migration and differentiation of human eosinophilic leukemia EoL-1 cells through PKCdelta activation. Mol Biol Rep 2010; 37(5): 2149-56.  Back to cited text no. 15
    
16.
Lee JS, Yang EJ, Kim IS. The roles of MCP-1 and protein kinase C delta activation in human eosinophilic leukemia EoL-1 cells. Cytokine 2009; 48(3): 186-95.  Back to cited text no. 16
    
17.
Yadav V, Denning MF. Fyn is induced by Ras/PI3K/Akt signaling and is required for enhanced invasion/migration. Mol Carcinog 2011; 50(5): 346-52.  Back to cited text no. 17
    
18.
Buitenhuis M. The role of PI3K/protein kinase B (PKB/c-akt) in migration and homing of hematopoietic stem and progenitor cells. Curr Opin Hematol 2011; 18(4): 226-30.  Back to cited text no. 18
    
19.
Tai YT, Podar K, Mitsiades N, Lin B, Mitsiades C, Gupta D, Akiyama M, Catley L, Hideshima T, Munshi NC, Treon SP, Anderson KC. CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling. Blood 2003; 101(7): 2762-9.  Back to cited text no. 19
    
20.
Zhu Y, Bertics PJ. Chemoattractant-induced signaling via the Ras-ERK and PI3K-Akt networks, along with leukotriene C4 release, is dependent on the tyrosine kinase Lyn in IL-5- and IL-3-primed human blood eosinophils. J Immunol 2011; 186(1): 516-26.  Back to cited text no. 20
    
21.
Jin Y, Chen Q, Lu Z, Chen B, Pan J. Triptolide abrogates oncogene FIP1L1-PDGFRalpha addiction and induces apoptosis in hypereosinophilic syndrome. Cancer Sci 2009; 100(11): 2210-7.  Back to cited text no. 21
    
22.
Mishra RK, Scaife JE, Harb Z, Gray BC, Djukanovic R, Dent G. Differential dependence of eosinophil chemotactic responses on phosphoinositide 3-kinase (PI3K). Allergy 2005; 60(9): 1204-7.  Back to cited text no. 22
    
23.
Pinho V, Souza DG, Barsante MM, Hamer FP, De Freitas MS, Rossi AG, Teixeira MM. Phosphoinositide-3 kinases critically regulate the recruitment and survival of eosinophils in vivo: importance for the resolution of allergic inflammation. J Leukoc Biol 2005; 77(5): 800-10.  Back to cited text no. 23
    
24.
Chen J, Tang H, Hay N, Xu J, Ye RD. Akt isoforms differentially regulate neutrophil functions. Blood 2010; 115(21): 4237-46.  Back to cited text no. 24
    
25.
Rane MJ, Klein JB. Regulation of neutrophil apoptosis by modulation of PKB/Akt activation. Front Biosci 2009; (14): 2400-12.  Back to cited text no. 25
    
26.
Liu W, Wu S. The roles of Akt and NOSs in regulation of VLA-4-mediated melanoma cell adhesion to endothelial VCAM-1 after UVB-irradiation. Arch Biochem Biophys 2011; 508(2): 192-7.  Back to cited text no. 26
    
27.
Los M, Maddika S, Erb B, Schulze-Osthoff K. Switching Akt: from survival signaling to deadly response. Bioessays 2009; 31(5): 492-5.  Back to cited text no. 27
    
28.
Li B, Zhang G, Li C, He D, Li X, Zhang C, Tang F, Deng X, Lu J, Tang Y, Li R, Chen Z, Duan C. Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL. PLoS One 2012; 7(4): e34912.  Back to cited text no. 28
    
29.
Kwon BC, Sohn MH, Kim KW, Kim ES, Kim KE, Shin MH. House dust mite induces expression of intercellular adhesion molecule-1 in EoL-1 human eosinophilic leukemic cells. J Korean Med Sci 2007; 22(5): 815-9.  Back to cited text no. 29
    
30.
Ip WK, Wong CK, Lam CW. Tumour necrosis factor-alpha-induced expression of intercellular adhesion molecule-1 on human eosinophilic leukaemia EoL-1 cells is mediated by the activation of nuclear factor-kappaB pathway. Clin Exp Allergy 2003; 33(2): 241-8.  Back to cited text no. 30
    
31.
Shalapour S, Hof J, Kirschner-Schwabe R, Bastian L, Eckert C, Prada J, Henze G, von Stackelberg A, Seeger K. High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse. Haematologica 2011; 96(11): 1627-35.  Back to cited text no. 31
    


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