Hypereosinophilic syndrome (HES) includes heterogeneous hematological disorders that are characterized by distinctive blood and tissue eosinophilia. In addition to classical HES criteria, the World Health Organization proposed a set of criteria that distinguish chronic eosinophilic leukemia (CEL) from HES. As such, the fusion gene FIP1L1/PDGFRA was found as a cause of CEL in a significant proportion of patients initially diagnosed as having HES. Several investigations have tried to dissect the mechanism of leukemogenesis; eosinophilia and signaling induced by FIP1L1/PDGFRα in cell lines, bone marrow mast cells, primary human eosinophils and in murine myeloproliferative disorder models. In this review, we introduce the current knowledge on the relationship between FIP1L1/PDGFRα and cell signaling, eosinophil proliferation, survival and activation and mastocytosis specially focusing on the evidence learned from murine models.

Keywords:
Eosinophil, Hypereosinophilic syndrome, Chronic eosinophilic leukemia, FIP1L1/PDGFRα
1.
Hardy WR, Anderson RE: The hypereosinophilic syndromes. Ann Intern Med 1968;68:1220–1229.
2.
Chusid MJ, Dale DC, West BC, Wolff SM: The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975;54:1–27.
3.
Bain B, Pierre R, Imbert M, Vardiman JW, Brunning RD, Flandrin G: Chronic Eosinophilic Leukaemia and the Hypereosinophilic Syndrome. Lyon, IARC Press, 2001.
4.
Schaller JL, Burkland GA: Case report: rapid and complete control of idiopathic hypereosinophilia with imatinib mesylate. MedGenMed 2001;3:9.
5.
Ault P, Cortes J, Koller C, Kaled ES, Kantarjian H: Response of idiopathic hypereosinophilic syndrome to treatment with imatinib mesylate. Leuk Res 2002;26:881–884.
6.
Cortes J, Ault P, Koller C, Thomas D, Ferrajoli A, Wierda W, Rios MB, Letvak L, Kaled ES, Kantarjian H: Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 2003;101:4714–4716.
7.
Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH: Treatment of hypereosinophilic syndrome with imatinib mesilate. Lancet 2002;359:1577–1578.
8.
Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter EJ, Witzig TE, Cross NC, Tefferi A: Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003;101:3391–3397.
9.
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;348:1201–1214.
10.
Griffin JH, Leung J, Bruner RJ, Caligiuri MA, Briesewitz R: Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci USA 2003;100:7830–7835.
11.
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;101:4660–4666.
12.
Maric I, Robyn J, Metcalfe DD, Fay MP, Carter M, Wilson T, Fu W, Stoddard J, Scott L, Hartsell M, Kirshenbaum A, Akin C, Nutman TB, Noel P, Klion AD: KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol 2007;120:680–687.
13.
Hubbard SR: Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol 2004;5:464–471.
14.
Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J: Activation of FIP1L1-PDGFRα requires disruption of the juxtamembrane domain of PDGFRα and is FIP1L1-independent. Proc Natl Acad Sci USA 2006;103:8078–8083.
15.
Roche-Lestienne C, Lepers S, Soenen-Cornu V, Kahn JE, Lai JL, Hachulla E, Drupt F, Demarty AL, Roumier AS, Gardembas M, Dib M, Philippe N, Cambier N, Barete S, Libersa C, Bletry O, Hatron PY, Quesnel B, Rose C, Maloum K, Blanchet O, Fenaux P, Prin L, Preudhomme C: Molecular characterization of the idiopathic hypereosinophilic syndrome in 35 French patients with normal conventional cytogenetics. Leukemia 2005;19:792–798.
16.
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;18:734–742.
17.
Li S, Gillessen S, Tomasson MH, Dranoff G, Gilliland DG, Van Etten RA: Interleukin-3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL. Blood 2001;97:1442–1450.
18.
Daley GQ, Van Etten RA, Baltimore D: Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990;247:824–830.
19.
Cools J, Quentmeier H, Huntly BJ, Marynen P, Griffin JD, Drexler HG, Gilliland DG: The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 2004;103:2802–2805.
20.
Verstovsek S, Giles FJ, Quintas-Cardama A, Manshouri T, Huynh L, Manley P, Cortes J, Tefferi A, Kantarjian H: Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR- α-expressing cells. Leuk Res 2006;30:1499–1505.
21.
Lierman E, Folens C, Stover EH, Mentens N, Van Miegroet H, Scheers W, Boogaerts M, Vandenberghe P, Marynen P, Cools J: Sorafenib is a potent inhibitor of FIP1L1-PDGFRα and the imatinib-resistant FIP1L1-PDGFRα T674I mutant. Blood 2006;108:1374–1376.
22.
Yamada Y, Sanchez-Aguilera A, Brandt EB, McBride M, Al-Moamen NJ, Finkelman FD, Williams DA, Cancelas JA, Rothenberg ME: FIP1L1/PDGFRα synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome. Blood 2008;112:2500–2507.
23.
Buitenhuis M, Verhagen LP, Cools J, Coffer PJ: Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation. Cancer Res 2007;67:3759–3766.
24.
Cools J, Stover EH, Boulton CL, Gotlib J, Legare RD, Amaral SM, Curley DP, Duclos N, Rowan R, Kutok JL, Lee BH, Williams IR, Coutre SE, Stone RM, DeAngelo DJ, Marynen P, Manley PW, Meyer T, Fabbro D, Neuberg D, Weisberg E, Griffin JD, Gilliland DG: PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease. Cancer Cell 2003;3:459–469.
25.
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/chronic eosinophilic leukemia-like disease. Blood 2006;107:4071–4079.
26.
Bank I, Amariglio N, Reshef A, Hardan I, Confino Y, Trau H, Shtrasburg S, Langevitz P, Monselise Y, Shalit M, Rechavi G: The hypereosinophilic syndrome associated with CD4+CD3– helper type 2 lymphocytes. Leuk Lymphoma 2001;42:123–133.
27.
Garrett JK, Jameson SC, Thomson B, Collins MH, Wagoner LE, Freese DK, Beck LA, Boyce JA, Filipovich AH, Villanueva JM, Sutton SA, Assa’ad AH, Rothenberg ME: Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004;113:115–119.
28.
Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, Schwartz LB, Rosenwasser LJ, Ring J, Griffin EF, Haig AE, Frewer PI, Parkin JM, Gleich GJ: Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358:1215–1228.
29.
Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB: Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood 2004;103:2939–2941.
30.
Owen WF, Rothenberg ME, Petersen J, Weller PF, Silberstein D, Sheffer AL, Stevens RL, Soberman RJ, Austen KF: Interleukin-5 and phenotypically altered eosinophils in the blood of patients with the idiopathic hypereosinophilic syndrome. J Exp Med 1989;170:343–348.
31.
Simon HU, Plotz SG, Dummer R, Blaser K: Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999;341:1112–1120.
32.
Lamkhioued B, Gounni AS, Aldebert D, Delaporte E, Prin L, Capron A, Capron M: Synthesis of type 1 (IFNγ) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils. Ann NY Acad Sci 1996;796:203–208.
33.
Tefferi A, Pardanani A: Imatinib therapy in clonal eosinophilic disorders, including systemic mastocytosis. Int J Hematol 2004;79:441–447.
34.
Robyn J, Lemery S, McCoy JP, Kubofcik J, Kim YJ, Pack S, Nutman TB, Dunbar C, Klion AD: Multilineage involvement of the fusion gene in patients with FIP1L1/ PDGFRA-positive hypereosinophilic syndrome. Br J Haematol 2006;132:286–292.
35.
Tefferi A, Lasho TL, Brockman SR, Elliott MA, Dispenzieri A, Pardanani A: FIP1L1-PDGFRA and c-kit D816V mutation-based clonality studies in systemic mast cell disease associated with eosinophilia. Haematologica 2004;89:871–873.
36.
Dent LA, Strath M, Mellor AL, Sanderson CJ: Eosinophilia in transgenic mice expressing interleukin-5. J Exp Med 1990;172:1425–1431.
37.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, Sultan C, Cox C: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 1994;87:746–754.
38.
Gotlib V, Darji J, Bloomfield K, Chadburn A, Patel A, Braunschweig I: Eosinophilic variant of chronic myeloid leukemia with vascular complications. Leuk Lymphoma 2003;44:1609–1613.
39.
Brito-Babapulle F: Clonal eosinophilic disorders and the hypereosinophilic syndrome. Blood Rev 1997;11:129–145.
40.
Von Bubnoff N, Gorantla SP, Thone S, Peschel C, Duyster J: The FIP1L1-PDGFRA T674I mutation can be inhibited by the tyrosine kinase inhibitor AMN107 (nilotinib). Blood 2006;107:4970–4972.
41.
Ohnishi H, Kandabashi K, Maeda Y, Kawamura M, Watanabe T: Chronic eosinophilic leukaemia with FIP1L1-PDGFRA fusion and T674I mutation that evolved from Langerhans cell histiocytosis with eosinophilia after chemotherapy. Br J Haematol 2006;134:547–549.
42.
Stein ML, Villanueva JM, Buckmeier BK, Yamada Y, Filipovich AH, Assa’ad AH, Rothenberg ME: Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels. J Allergy Clin Immunol 2008;121:1473–1483, e1471–e1474.
43.
Aizawa H, Zimmermann N, Carrigan PE, Lee JJ, Rothenberg ME, Bochner BS: Molecular analysis of human Siglec-8 orthologs relevant to mouse eosinophils: identification of mouse orthologs of Siglec-5 (mSiglec-F) and Siglec-10 (mSiglec-G). Genomics 2003;82:521–530.
44.
Zhang JQ, Biedermann B, Nitschke L, Crocker PR: The murine inhibitory receptor mSiglec-E is expressed broadly on cells of the innate immune system whereas mSiglec-F is restricted to eosinophils. Eur J Immunol 2004;34:1175–1184.
45.
Zimmermann N, McBride ML, Yamada Y, Hudson SA, Jones C, Cromie KD, Crocker PR, Rothenberg ME, Bochner BS: Siglec-F antibody administration to mice selectively reduces blood and tissue eosinophils. Allergy 2008;63:1156–1163.
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2009
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