Use of the term ‘idiopathic hypereosinophilic syndrome (HES)’ has highlighted our basic lack of understanding of the molecular pathophysiology of eosinophilic disorders. However, over the last 10 years, the study of hypereosinophilia has enjoyed a revival. This interest has been rekindled by two factors: (1) the development of increasingly sophisticated molecular biology techniques that have unmasked recurrent genetic abnormalities linked to eosinophilia, and (2) the successful application of targeted therapy with agents such as imatinib to treat eosinophilic diseases. To date, most of these recurrent molecular abnormalities have resulted in constitutively activated fusion tyrosine kinases whose phenotypic consequence is an eosinophilia-associated myeloid disorder. Most notable among these are rearrangements of platelet-derived growth factor receptors α and β (PDGFRα, PDGFRβ), which define a small subset of patients with eosinophilic chronic myeloproliferative disorders (MPDs) and/or overlap myelodysplastic syndrome/MPD syndromes, including chronic myelomonocytic leukemia. Discovery of the cryptic FIP1L1-PDGFRA gene fusion in cytogenetically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES has redefined these diseases as clonal eosinophilias. A growing list of fibroblast growth factor receptor 1 fusion partners has similarly emerged in the 8p11 myeloproliferative syndromes, which are often characterized by elevated eosinophil counts. Herein the focus is on the molecular gains made in these MPD-type eosinophilias, and the classification and clinicopathological issues related to hypereosinophilic syndromes, including the lymphocyte variant. Success in establishing the molecular basis of a group of once seemingly heterogeneous diseases has now the laid the foundation for establishing a semi-molecular classification scheme of eosinophilic disorders.

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 1975;54:1–27.
3.
Bain B, Pierre R, Imbert M, Vardiman JW, Brunning RD, Flandrin G: Chronic eosinophilic leukaemia and the hypereosinophilic syndrome; in Jaffe ES, Harris NL, Stein H, Vardiman JW (eds): World Health Organization of Tumours: Tumours of Haematopoietic and Lymphoid tissues. Lyon, IARC Press, 2001, pp 29–31.
4.
Roufosse F, Cogan E, Goldman M: Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy 2004;59:673–689.
5.
Forrest DL, Horsman DE, Jensen CL, et al: Myelodysplastic syndrome with hypereosinophilia and a nonrandom chromosomal abnormality dic(1;7): Confirmation of eosinophil clonal involvement by fluorescence in situ hybridization. Cancer Genet Cytogenet 1998;107:65–68.
6.
Goldman JM, Najfeld V, Th’ng KH: Agar culture and chromosome analysis of eosinophilic leukaemia. J Clin Pathol 1975;28:956–961.
7.
Chang HW, Leong KH, Koh DR, Lee SH: Clonality of isolated eosinophils in the hypereosinophilic syndrome. Blood 1999;93:1651–1657.
8.
Luppi M, Marasca R, Morselli M, Barozzi P, Torelli G: Clonal nature of hypereosinophilic syndrome. Blood 1994;84:349–350.
9.
Schoch C, Reiter A, Bursch S, et al: Chromosome banding analysis, FISH and RT-PCR performed in parallel in hypereosinophilic syndrome establishes the diagnosis of chronic eosinophilic leukemia in 22% of cases: A study on 40 patients (abstract). Blood 2004;104:671a.
10.
Pardanani A, Ketterling RP, Brockman SR, et al: CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib therapy. Blood 2003;102:3093–3096.
11.
Tefferi A, Lasho TL, Brockman SR, et al: FIP1L1-PDGFRA and c-kit D816V mutation-based clonality studies in systemic mast cell disease associated with eosinophilia. Haematologica 2004;89:871–873.
12.
Lemery SJ, Robyn JA, McCoy P, et al: Lineage analysis of the FIP1L1-PDGFRa fusion gene in myeloproliferative hypereosinophilic syndrome (abstract). Blood 2004;104:670a–671a.
13.
Kawasaki A, Mizushima Y, Matsui S, Hoshino K, Yano S, Kitagawa M: A case of T-cell lymphoma accompanying marked eosinophilia, chronic eosinophilic pneumonia and eosinophilic pleural effusion. A case report. Tumori 1991;77:527–530.
14.
Endo M, Usuki K, Kitazume K, Iwabe K, Okuyama Y, Urabe A: Hypereosinophilic syndrome in Hodgkin’s disease with increased granulocyte-macrophage colony-stimulating factor. Ann Hematol 1995;71:313–314.
15.
Catovksy D, Bernasconi C, Verdonck PJ, et al: The association of eosinophilia with lymphoblastic leukaemia or lymphoma: A study of seven patients. Br J Haematol 1980;45:523–534.
16.
Takai K, Sanada M: Hypereosinophilic syndrome evolving to acute lymphoblastic leukemia. Int J Hematol 1991;54:231–239.
17.
Bain BJ: Cytogenetic and molecular genetic aspects of eosinophilic leukaemias. Br J Haematol 2003;122:173–179.
18.
Cools J, DeAngelo DJ, Gotlib J, et al: 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.
19.
Park CY, Chung CH, Park YJ: Chronic eosinophilic leukemia with 46,XY,1,der(1;7)(q10;p10). Ann Hematol 2004;83:547–548.
20.
Hermida G, Manjon R, Rodriguez-Salazar M, Calasanz MJ: Hypereosinophilia associated with dysplastic features and a constitutional translocation previously not described. Haematologica 2000;85:997–998.
21.
Musto P, Falcone A, Sanpaolo G, et al: Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: Implications for dosing and pathogenesis. Leuk Lymphoma 2004;45:1219–1222.
22.
Myint H, Chacko J, Mould S, Ross F, Oscier DG: Karyotypic evolution in a granulocytic sarcoma developing in a myeloproliferative disorder with a novel (3;4) translocation. Br J Haematol 1995;90:462–464.
23.
Shanske AL, Kalman A, Grunwald H: A myeloproliferative disorder with eosinophilia associated with a unique translocation (3;5). Br J Haematol 1996;95:524–526.
24.
Duell T, Mittermuller J, Schmetzer HM, Kolb HJ, Wilmanns W: Chronic myeloid leukemia associated hypereosinophilic syndrome with a clonal t(4;7)(q11;q32). Cancer Genet Cytogenet 1997;94:91–94.
25.
Schoffski P, Ganser A, Pascheberg U, Busche G, Gaede B, Hertenstein B: Complete haematological and cytogenetic response to interferon alpha-2a of a myeloproliferative disorder with eosinophilia associated with a unique t(4;7) aberration. Ann Hematol 2000;79:95–98.
26.
Hild F, Fonatsch C: Cytogenetic peculiarities in chronic myelogenous leukemia. Cancer Genet Cytogenet 1990;47:197–217.
27.
Bakhshi S, Hamre M, Mohamed AM, Feldman G, Ravindranath Y: t(5;9)(q11;q34): A novel familial translocation involving Abelson oncogene and association with hypereosinophilia. J Pediatr Hematol Oncol 2003;25:82–84.
28.
Yoo TJ, Orman SV, Patil SR, et al: Evolution to eosinophilic leukemia with a t(5;11) translocation in a patient with idiopathic hypereosinophilic syndrome. Cancer Genet Cytogenet 1984;11:389–394.
29.
Suzuki S, Chiba K, Toyoshima N, et al: Chronic eosinophilic leukemia with t(6;11)(q27;q23) translocation. Ann Hematol 2001;80:553–556.
30.
Presti C, Ryan T, Armstrong WF: Two dimensional and Doppler echocardiographic findings in hypereosinophilic syndrome. Am Heart J 1987;114:172–175.
31.
da Silva MA, Heerema N, Schwenk GR Jr, Hoffman R: Evidence for the clonal nature of hypereosinophilic syndrome. Cancer Genet Cytogenet 1988;32:109–115.
32.
Vandenberghe P, Wlodarska I, Michaux L, et al: Clinical and molecular features of FIP1L1-PDGFRA (+) chronic eosinophilic leukemias. Leukemia 2004;18:734–742.
33.
Kobayashi H, Kitano K, Shimodaira S, et al: Eosinophilia in myelodysplastic syndrome with a t(12;21)(q23;q22) translocation. Cancer Genet Cytogenet 1993;68:95–98.
34.
Brito-babapulle F, Butler TA, Secker-Walker L, Goldman JM: Eosinophilic myelodysplastic syndrome: An entity to be distinguished from the idiopathic hypereosinophilic syndrome (abstract). Blood 1997;90:285b.
35.
Ishii Y, Ito Y, Kuriyama Y, Tauchi T, Ohyashiki K: Successful treatment with imatinib mesylate of hypereosinophilic syndrome (chronic eosinophilic leukemia) with myelofibrosis. Leuk Res 2004;28(suppl 1):S79–S80.
36.
Bigoni R, Cuneo A, Roberti MG, et al: Cytogenetic and molecular characterization of 6 new cases of idiopathic hypereosinophilic syndrome. Haematologica 2000;85:486–491.
37.
Humphrey MJ, Hutter JJ, Tom WW: Hypereosinophilia in a monosomy 7 myeloproliferative disorder in childhood. Am J Hematol 1981;11:107–110.
38.
Viniou N, Yataganas X, Abazis D, et al: Hypereosinophilia associated with monosomy 7. Cancer Genet Cytogenet 1995;80:68–71.
39.
Maubach PA, Bauchinger M, Emmerich B, Rastetter J: Trisomy 7 and 8 in Ph-negative chronic eosinophilic leukemia. Cancer Genet Cytogenet 1985;17:159–164.
40.
Weinfeld A, Westin J, Swolin B: Ph1-negative eosinophilic leukemia with trisomy 8. Scand J Haematol 1977;18:413–420.
41.
Parreira L, Tavares de Castro J, Hibbin JA, et al: Chromosome and cell culture studies in eosinophilic leukaemia. Br J Haematol 1986;62:659–669.
42.
Michel G, Thuret I, Capodano AM, et al: Myelofibrosis in a child suffering from a hypereosinophilic syndrome with trisomy 8: Response to corticotherapy. Med Pediatr Oncol 1991;19:62–65.
43.
Guitard AM, Horschowski N, Mozziconacci MJ, et al: Hypereosinophilic syndrome in childhood: Trisomy 8 and transformation to mixed acute leukaemia. Nouv Rev Fr Hematol 1994;35:555–559.
44.
Ribeiro I, Carvalho IR, Fontes M, et al: Eosinophilic leukaemia with trisomy 8 and double gammopathy. J Clin Pathol 1993;48:672–673.
45.
Quiquandon I, Claisse JF, Capiod JC, Delobel J, Prin L: Alpha-interferon and hypereosinophilic syndrome with trisomy 8: Karyotypic remission. Blood 1995;85:2284–2285.
46.
Ma SK, Kwong YL, Shek TW, et al: The role of trisomy 8 in the pathogenesis of chronic eosinophilic leukemia. Hum Pathol 1999;30:864–868.
47.
Pardanani A, Reeder T, Porrata L, et al: Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003;101:3391–3397.
48.
Salem Z, Zalloua PA, Chehal A, et al: Effective treatment of hypereosinophilic syndrome with imatinib mesylate. Leuk Res 2003;4:410–412.
49.
Kook H, Cho D, Noh H-Y, et al: Chronic eosinophilic leukemia with unique chromosomal abnormality, add(8)(p23), in a 14-month girl: Treatment with imatinib mesylate (abstract). Blood 2002;100:344b.
50.
Egesten A, Hagerstrand I, Kristoffersson U, Garwicz S: Hypereosinophilic syndrome in a child mosaic for a congenital triplication of the short arm of chromosome 8. Br J Haematol 1997;96:369–373.
51.
Mori Y, Ebira H, Shindo Y, Saita R, Kitamura H: Eosinophilic leukemia with trisomy no. 8 and no. 9 chromosomes: Report of a case. Rinsho Ketsueki 1986;27:565–569.
52.
Kueck BD, Smith RE, Parkin J, Peterson LC, Hanson CA: Eosinophilic leukemia: A myeloproliferative disorder distinct from the hypereosinophilic syndrome. Hematol Pathol 1991;5:195–205.
53.
Oliver JW, Deol I, Morgan DL, Tonk VS: Chronic eosinophilic leukemia and hypereosinophilic syndromes. Proposal for classification, literature review, and report of a case with a unique chromosomal abnormality. Cancer Genet Cytogenet 1998;107:111–117.
54.
Weide R, Rieder H, Mehraein Y, et al: Chronic eosinophilic leukaemia (CEL): A distinct myeloproliferative disease. Br J Haematol 1997;96:117–123.
55.
Mitelman F, Panari A, Brandt L: Isochromosome 17 in a case of eosinophilic leukaemia. Scand J Haematol 1975;14:308–312.
56.
Cabrol C: Chromosomal anomaly in eosinophilic leukemia. N Engl J Med 1979;301:439.
57.
Lönnqvist B, Gahrton G, Erikkson P, Friberg K, Zech L: Isochromosome 17 in a patient with a myeloproliferative disorder terminating in eosinophilic leukemia. Acta Med Scand 1979;206:321–325.
58.
Rotoli B, Catalano L, Galderisi M, et al: Rapid reversion of Loeffler’s endocarditis by imatinib in early stage clonal hypereosinophilic syndrome. Leuk Lymphoma 2004;45:2503–2507.
59.
Brigaudeau C, Liozon E, Bernard P, Trimoreau F, Bordessoule D, Praloran V: Deletion of chromosome 20q associated with hypereosinophilic syndrome. A report of two cases. Cancer Genet Cytogenet 1996;87:82–84.
60.
Kusanagi Y, Ochi H, Matsubara K, Ito M: Hypereosinophilic syndrome in a trisomy 21 fetus. Obstet Gynecol 1998;92:701–702.
61.
Needleman SW, Mane SM, Gutheil JC, Kapil V, Heyman MR, Testa JR: Hypereosinophilic syndrome with evolution to myeloproliferative disorder: Temporal relationship to loss of Y chromosome and c-N-ras activation. Hematol Pathol 1990;4:149–155.
62.
Pardanani A, Brockman SR, Paternoster SF, et al: FIP1L1-PDGFRA fusion: Prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004;104:3038–3045.
63.
Goffman TE, Mulvihill JJ, Carney DN, et al: Fatal hypereosinophilia with chromosome 15q– in a patient with multiple primary and familial neoplasms. Cancer Genet Cytogenet 1983;8:197–202.
64.
Flannery EP, Dillon DE, Freeman MV, Levy JD, D’Ambrosio U, Bedynek JL: Eosinophilic leukemia with fibrosing endocarditis and short Y chromosome. Ann Intern Med 1972;77:223–228.
65.
Bitran JD, Rowley JD, Plapp F, Golomb HM, Ultmann JE: Chromosomal aneuploidy in a patient with hypereosinophilic syndrome. Evidence for a malignant disease. Am J Med 1977;63:1010–1014.
66.
Huang CS, Gomez GA, Kohno SI, et al: Chromosomes and causation of human cancer and leukemia. XXXIV. A case of ‘hypereosinophilic syndrome’ with unusual cytogenetic findings in a chloroma, terminating in blastic transformation and CNS leukemia. Cancer 1979;44:1284–1289.
67.
Ellman L, Hammond D, Atkins L: Eosinophilia, chloromas, and a chromosome abnormality in a patient with a myeloproliferative syndrome. Cancer 1979;43:2410–2413.
68.
Goh KO, Ho FS, Tso SC, Ma J: Is hypereosinophilic syndrome a malignant disease? Cancer 1985;55:2395–2399.
69.
Mitter NS, Weiskopf RW: Unusual chromosome 7 aberrations in a case of eosinophilic myeloproliferative syndrome. Cancer Genet Cytogenet 1987;26:209–212.
70.
Wolz DE, Granato JE, Giles HR, Marks SM, Grill HP: A unique chromosomal abnormality in idiopathic hypereosinophilic syndrome presenting with cardiac involvement. Am Heart J 1993;126:246–248.
71.
Musto P, Perla G, Minervini MM, Carella AM: Imatinib-mesylate for all patients with hypereosinophilic syndrome. Leuk Res 2004;28:773–774.
72.
Pardanani A, Reeder T, Li CY, Tefferi A: Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia. Leuk Res 2003;27:883–885.
73.
Le Beau MM, Larson RA, Bitter MA, Vardiman JW, Golomb HM, Rowley JD: Association of inversion 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. N Engl J Med 1983;309:630–636.
74.
Swirsky DM, Li YS, Matthews JG, Flemans RJ, Rees JKH, Hayhoe FGJ: 8;21 translocation in acute granulocytic leukemia: Cytological, cytochemical, and clinical features. Br J Haematol 1984;56:199–213.
75.
Song HS, Park SK: A case of monosomy-7 eosinophilic leukemia and neurofibromatosis, terminated with disseminated cryptococcosis. Korean J Intern Med 1987;2:131–134.
76.
Harrington DS, Peterson C, Ness M, Sanger W, Smith DM, Vaughan W: Acute myelogenous leukemia with eosinophilic differentiation and trisomy-1. Am J Clin Pathol 1988;90:464–469.
77.
Broustet A, Bernard P, Dachary D, et al: Acute eosinophilic leukemia with a translocation (10p+;11q–). Cancer Genet Cytogenet 1986;1:327–333.
78.
Bhambhani K, Inoue S, Tyrkus M, Gohle N: Acute myelomonocytic leukemia type M4 with bone marrow eosinophilia and t(5;16)(q33;q22). Cancer Genet Cytogenet 1986;20:187–188.
79.
Mecucci C, Bosly A, Michaux JL, Broeckaert-Van Orshoven A, Van den Berghe H: Acute nonlymphoblastic leukemia with bone marrow eosinophilia and structural anomaly of chromosome 16. Cancer Genet Cytogenet 1985;17:359–363.
80.
Matsushima T, Murakami H, Kim K, et al: Steroid-responsive pulmonary disorders associated with myelodysplastic syndromes with der(1q;7p) chromosomal abnormality. Am J Hematol 1995;50:110–115.
81.
Reilly JT: Class III receptor tyrosine kinases: Role in leukaemogenesis. Br J Haematol 2002;116:744–757.
82.
Yarden Y, Escobedo JA., Kuang W-J, et al: Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature 1986;323:226–232.
83.
Yoon SY, Tefferi A, Li CY: Cellular distribution of platelet-derived growth factor, transforming growth factor-beta, basic fibroblast growth factor, and their receptors in normal bone marrow. Acta Haematol 2000;104:151–157.
84.
Heldin C-H, Westermark B: Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 1999;79:1283–1316.
85.
Claesson-Welsh L: Platelet-derived growth factor receptor signals. J Biol Chem 1994;269:32023–32026.
86.
Li X, Ponten A, Aase K, et al: PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. Nat Cell Biol 2000;2:302–309.
87.
Bergsten E, Uuetela M, Li X, et al: PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol 2001;3:512–516.
88.
LaRochelle WJ, Jeffers M, McDonald WF, et al: PDGF-D, a new protease-activated growth factor. Nat Cell Biol 2001;3:517–521.
89.
Heldin CH, Ostman A, Ronnstrand L: Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1998;1378:F79–F113.
90.
Valgeirsdottir S, Paukku K, Silvennoinen O, et al: Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF beta-receptor juxtamembrane and kinase insert domains. Oncogene 1998;16:505–515.
91.
Sachsenmaier C, Sadowski HB, Cooper JA: STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation. Oncogene 1999;18:3583–3592.
92.
Golub TR, Barker GF, Lovett M, et al: Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994;77:307–316.
93.
Abe A, Emi N, Tanimoto M, et al: Fusion of the platelet-derived growth factor beta receptor to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. Blood 1997;90:4271–4277.
94.
Ross TS, Bernard OA, Berger R, et al: Fusion of Huntington interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2). Blood 1998;91:4419–4426.
95.
Schwaller J, Anastasiadou E, Cain D, et al: H4/D10S170, a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). Blood 2001;97:3910–3918.
96.
Kulkarni S, Heath C, Parker S, et al: Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer Res 2000;60:3592–3598.
97.
Magnusson MK, Meade KE, Brown KE, et al: Rabaptin-5 is a novel fusion partner to platelet-derived growth factor receptor beta in chronic myelomonocytic leukemia. Blood 2001;98:2518–2525.
98.
Baxter EJ, Kulkarni S, Vizmanos JL, et al: Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders. Br J Haematol 2003;120:251–256.
99.
Wilkinson K, Velloso ER, Lopez LF, et al: Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: Involvement of PDGFRB and response to imatinib. Blood 2003;102:4187–4190.
100.
Morerio C, Acquila M, Rosanda C, et al: HCMOGT-1 is a novel fusion partner to PDGFRB in juvenile myelomonocytic leukemia with t(5;17)(q33;p11.2). Cancer Res 2004;64:2649–2651.
101.
Vizmanos JL, Novo FJ, Roman JP, et al: NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder. Cancer Res 2004;64:2673–2676.
102.
Grand FH, Burgstaller S, Kuhr T, et al: P53-binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder. Cancer Res 2004;64:7216–7219.
103.
Ketterling RP, Knudson RA, Gilmer HCF: Discovery of 6 novel translocations involving the imatinib responsive genes PDGFRA and PDGFRB from screening 29,047 abnormal bone marrow specimens (abstract). Blood 2004;104:793a.
104.
Levine RL, Wadleigh M, Sternberg DW, et al: KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). Leukemia 2005;19:27–30.
105.
Steer EJ, Cross NC: Myeloproliferative disorders with translocations of chromosome 5q31–5q35: Role of the platelet-derived growth factor receptor beta. Acta Haematol 2002;107:113–122.
106.
Ross TS, Gilliland DG: Transforming properties of the Huntingtin interacting protein 1/platelet-derived growth factor beta receptor fusion protein. J Biol Chem 1999;274:22328–22336.
107.
Baxter EJ, Hochhaus A, Bolufer P, et al: The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum Mol Genet 2002;11:1391–1397.
108.
Trempat P, Villalva C, Laurent G, et al: Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: A new clinical target for STI571/Glivec. Oncogene 2003;22:5702–5706.
109.
Safley AM, Sebastian S, Collins TS, et al: Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-de rived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia. Genes Chromosomes Cancer 2004;40:44–50.
110.
Schaller JL, Burkland GA: Case report: Rap id and complete control of idiopathic hypereosinophilia with imatinib mesylate. MedGenMed 2001;3:9.
111.
Gleich GJ, Leiferman KM, Pardanani A, Tefferi A, Butterfield JH: Treatment of hypereosinophilic syndrome with imatinib mesylate. Lancet 2002;359:1577–1578.
112.
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.
113.
Nolasco I, Carvalho S, Parreira A: Rapid and complete response to imatinib mesylate (STI-571) in a patient with idiopathic hypereosinophilia (abstract). Blood 2002;100:346b.
114.
Cortes J, Ault P, Koller C, et al: Efficacy of imatinib mesylate in the treatment of idiopathic hypereosinophilic syndrome. Blood 2003;101:4714–4716.
115.
Preker PJ, Lingner J, Minvielle-Sebastia L, Keller W: The FIP1 gene encodes a component of a yeast pre-mRNA polyadenylation factor that directly interacts with poly(A) polymerase. Cell 1995;81:379–389.
116.
Martinelli G, Cilloni D, Ottaviani E, et al: Idiopathic hypereosinophilic syndrome (HES) with FIP1L1-PDGFRA rearrangement can be effectively treated with imatinib (abstract). Blood 2004;104:421a.
117.
Martinelli G, Apperley J, Reiter A, et al: European multicenter experience on idiopathic hypereosinophilic syndrome (HES) with FIP1L1-PDGFRA rearrangement treated with imatinib (abstract). Blood 2004;104:422a.
118.
Roche-Lestienne C, Soenen-Cornu V, Kahn J-E, et al: Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics (abstract). Blood 2004;104:671a.
119.
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.
120.
Cools J, Quentmeier H, Huntly BJP, et al: 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.
121.
Gotlib J, Cools J, Malone JM, et al: The FIP1L1-PDGFRα fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: Implications for diagnosis, classification, and management. Blood 2004;103:2879–2891.
122.
Walz C, Cilloni D, Soverini S, et al: Molecular heterogeneity of the FIP1L1-PDGFRA fusion gene in chronic eosinophilic leukemia (CEL) and systemic mastocytosis with eosinophilia (SME): A study of 43 cases (abstract). Blood 2004;104:667a.
123.
Zhang GS, Li B, Pei MF, et al: Identification of FIP1L1-PDGFRA fusion, and expression of signal transducer and activator of transcription 5 in hypereosinophilic syndrome. Zhonghua Yi Xue Za Zhi 2004;84:1541–1544.
124.
Yu J, Deuel TF, Kim HR: Platelet-derived growth factor (PDGF) receptor-alpha activates c-Jun NH2-terminal kinase-1 and antagonizes PDGF receptor-beta-induced phenotypic transformation. J Biol Chem 2000;275:19076–19082.
125.
Yang J, Symes K, Mercola M, Schreiber SL: Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment. Curr Biol 1998;8:11–18.
126.
Stover EH, Cools J, Gilliland DG: Mechanisms of activation of the FIP1L1-PDGFRα fusion kinase (abstract). Blood 2004;104:666a.
127.
Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood 2002;100:1532–1542.
128.
Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations in c-kit in human gastrointestinal tumors. Science 1998;279:577–580.
129.
Irusta PM, Luo Y, Bakht O, Lai CC, Smith SO, DiMaio D: Definition of an inhibitory juxtamembrane WW-like domain in the platelet-derived growth factor beta receptor. J Biol Chem 2002;277:38627–38634.
130.
Heinrich MC, Corless CL, Duensing A, et al: PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708–710.
131.
Klion AD, Robyn J, Akin C, et al: Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 2004;103:473–478.
132.
Malagola M, Martinelli G, Rondoni M, et al: Soft tissue and skeletal involvement in FIP1L1-PDGFR-alpha positive chronic eosinophilic leukemia: imatinib mesylate may induce complete molecular and imaging remission. Haematologica 2004;89:ECR25.
133.
Martinelli G, Malagola M, Ottaviani E, et al: Imatinib mesylate can induce complete molecular remission in FIP1L1-PDGFR-α positive idiopathic hypereosinophilic syndrome. Haematologica 2004;89:236–237.
134.
Rose C, Dupire S, Roche-Lestienne C, et al: Sustained molecular response with imatinib in a leukemic form of idiopathic hypereosinophilic syndrome in relapse after allograft. Leukemia 2004;18:354–355.
135.
Frickhofen N, Marker-Hermann E, Reiter A, et al: Complete molecular remission of chronic eosinophilic leukemia complicated by CNS disease after targeted therapy with imatinib. Ann Hematol 2004;83:477–480.
136.
Von Bubnoff N, Sandherr M, Schlimok G, et al: Myeloid blast crisis evolving during imatinib treatment of an FIP1L1-PDGFR alpha-positive chronic myeloproliferative disease with prominent eosinophilia. Leukemia 2005;19:286–287.
137.
Cools J, Stover EH, Boulton CL, et al: PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRA-induced myeloproliferative disease. Cancer Cell 2003;3:459–469.
138.
Klion AD, Noel P, Akin C, et al: 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.
139.
Keene P, Mendelow B, Pinto MR, et al: Abnormalities of chromosome 12p13 and malignant proliferation of eosinophils: A non-random association. Br J Haematol 1987;67:25–31.
140.
Greipp PT, Dewald GW, Tefferi A: Prevalence, breakpoint distribution, and clinical correlates of t(5;12). Cancer Genet Cytogenet 2004;153:170–172.
141.
Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002;347:481–487.
142.
Pitini V, Arrigo C, Teti D, et al: Response to STI571 in chronic myelomonocytic leukemia with platelet derived growth factor beta receptor involvement: A new case report. Haematologica 2003;88:ECR18.
143.
Wittman B, Horan J, Baxter J, et al: A 2-year-old with atypical CML with a t(5;12)(q33;p13) treated successfully with imatinib mesylate. Leuk Res 2004;28(suppl 1):S65–S69.
144.
Garcia JL, Font de Mora J, Hernandez JM, et al: Imatinib mesylate elicits positive clinical response in atypical chronic myeloid leukemia involving the platelet-derived growth factor receptor beta. Blood 2003;102:2699–2700.
145.
Bastie JN, Garcia I, Terre C, et al: Lack of response to imatinib mesylate in a patient with accelerated phase myeloproliferative disorder with rearrangement of the platelet-derived growth factor receptor beta-gene. Haematologica 2004;89:1263–1264.
146.
Magnusson MK, Meade KE, Nakamura R, Barrett J, Dunbar CE: Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor β receptor fusion oncogene. Blood 2002;100:1088–1091.
147.
Sato H, Danbara M, Tamura M, Morita M: Eosinophilic leukemia with a t(2;5)(p23;q35) translocation. Br J Haematol 1994;87:404–406.
148.
Darbyshire PJ, Shortland D, Swansbury GJ, Sadler J, Lawler SD, Chessells JM: A myeloproliferative disease in two infants associated with eosinophilia and chromosome t(1;5) translocation. Br J Haematol 1987;66:483–486.
149.
Jani K, Kempski HM, Reeves BR: A case of myelodysplasia with eosinophilia having a translocation t(5;12)(q31;q13) restricted to myeloid cells but not involving eosinophils. Br J Haematol 1994;87:57–60.
150.
Cools J, Mentens N, Odero MD, et al: Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13). Blood 2002;99:1776–1784.
151.
Yoneda-Kato N, Look AT, Kirstein MN, et al: The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996;12:265–275.
152.
Borkhardt A, Bojesen S, Haas OA, et al: The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Proc Natl Acad Sci USA 2000;97:9168–9173.
153.
Taki T, Kano H, Taniwaki M, et al: AF5q31, a newly identified AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13a23). Proc Natl Acad Sci USA 1999;96:14535–14540.
154.
Jaju RJ, Fidler C, Haas OA, et al: A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 2001;98;1264–1267.
155.
Yagasaki F, Jinnai I, Yoshida S, et al: Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Genes Chromosomes Cancer 1999;26:192–202.
156.
Meeker TC, Hardy D, Willman C, Hogan T, Abrams J: Activation of the interleukin-3 gene by chromosome translocation in acute lymphoblastic leukemia with eosinophilia. Blood 1990;76:285–289.
157.
Keung YK, Beaty M, Steward W, Jackle B, Pettnati M: Chronic myelocytic leukemia with eosinophilia, t(9;12)(q34;p13) and ETV6-ABL gene rearrangement: Case report and review of the literature. Cancer Genet Cytogenet 2002;138:139–142.
158.
La Starza R, Trubia M, Testoni N, et al: Clonal eosinophils are a morphologic hallmark of ETV6/ABL1 positive acute myeloid leukemia. Haematologica 2002;87:789–794.
159.
Cazzaniga G, Tosi S, Aloisi A, et al: The tyrosine kinase abl-related gene ARG is fused to ETV6 in an AML-M4Eo with a t(1;12)(q25;p13): Molecular cloning of both reciprocal transcripts. Blood 1999;94:4370–4373.
160.
Kuno Y, Abe A, Emi N, et al: Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12). Blood 2001;97:1050–1055.
161.
Macdonald D, Reiter A, Cross NCP: The 8p11 myeloproliferative syndrome: A distinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol 2002;107:101–107.
162.
Popovici C, Adelaide J, Ollendorff V, et al: Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13). Proc Natl Acad Sci USA 1998;95:5712–5717.
163.
Reiter A, Sohal J, Kulkarni S, et al: Consistent fusion of ZNF198 to the fibroblast growth factor receptor 1 in the t(8;13)(p11;q12) myeloproliferative syndrome. Blood 1998;92:1735–1742.
164.
Smedley D, Hamoudi R, Clark J, et al: The t(8;13)(p11;q11–12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP. Hum Mol Genet 1998;7:637–642.
165.
Xiao S, Nalabolu SR, Aster JC, et al: FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome. Nat Genet 1998;18:84–87.
166.
Popovici C, Zhang B, Gregoire MJ, et al: The t(6;8)(q27;p11) translocation in a stem cell myeloproliferative disorder fuses a novel gene, FOP, to fibroblast growth factor receptor 1. Blood 1999;93:1381–1389.
167.
Guasch G, Mack GJ, Popovici C, et al: FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33). Blood 2000;95:1788–1796.
168.
Demiroglu A, Steer EJ, Heath C, et al: The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: Transforming activity and specific inhibition of FGFR1 fusion proteins. Blood 2001;98:3778–3783.
169.
Fioretos T, Panagopoulos I, Lassen C, et al: Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: The first fusion gene involving BCR but not ABL. Genes Chromosomes Cancer 2001;32:302–310.
170.
Guasch G, Popovici C, Mugneret F, et al: Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3). Blood 2003;101:286–288.
171.
Grand EK, Grand FH, Chase AJ, et al: Identification of a novel gene, FGFR1OP2, fused to FGFR1 in 8p11 myeloproliferative syndrome. Genes Chromosomes Cancer 2004;40:78–83.
172.
Belloni E, Trubia M, Gasparini P, et al: 8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes. Genes Chromosomes Cancer 2005;42:320–325.
173.
Sohal J, Chase A, Mould S, et al: Identification of four new translocations involving FGFR1 in myeloid disorders. Genes Chromosomes Cancer 2001;32:155–163.
174.
Mason IJ: The ins and outs of fibroblast growth factors. Cell 1994;78:547–552.
175.
Ollendorff V, Guasch G, Isnardon D, et al: Characterization of FIM-FGFR1, the fusion product of the myeloproliferative disorder-associated t(8;13) translocation. J Biol Chem 1999;274:26922–26930.
176.
Smedley D, Demiroglu A, Abdul-Rauf M, et al: ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATs 1 and 5. Neoplasia 1999;1:349–355.
177.
Roumiantsev S, Krause DS, Neumann CA, et al: Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. Cancer Cell 2004;5:287–298.
178.
Chen J, DeAngelo DJ, Kutok JL, et al: PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci USA 2004;101:14479–14484.
179.
Rothenberg ME: Eosinophilia. N Engl J Med 1998;338:1592–1600.
180.
Cogan E, Schandene L, Crusiaux A, Cochaux P, Velu T, Goldman M: Brief report: Clonal proliferation of type 2 helper T cells in a man with the hypereosinophilic syndrome. N Engl J Med 1994;330:535–538.
181.
Simon HU, Yousefi S, Dommann-Scherrer CC, et al: Expansion of cytokine-producing CD4–CD8– T cells associated with abnormal Fas expression and hypereosinophilia. J Exp Med 1996;183:1071–1082.
182.
Brugnoni D, Airo P, Rossi G, et al: CD4+ T-cell population able to secrete large amounts of interleukin-5. Blood 1996;87:1416–1422.
183.
Roufosse F, Schandene L, Sibille C, et al: T-cell receptor-independent activation of clonal Th2 cells associated with chronic hypereosinophilia. Blood 1999;94:994–1002.
184.
Bank I, Amariglio N, Reshef, A, et al: The hypereosinophilic syndrome associated with CD4+CD3– helper type 2 (Th2) lymphocytes. Leuk Lymphoma 2001;42:123–133.
185.
Simon HU, Plotz SG, Dummer R, Blaser K: Abnormal clones of T cells producing interleukin-5 in idiopathic hypereosinophilia. N Engl J Med 1999;341:1112–1120.
186.
Brugnoni D, Airo P, Tosoni C, et al: CD3–CD4+ cells with a Th2-like pattern of cytokine production in the peripheral blood of a patient with cutaneous T cell lymphoma. Leukemia 1997;11:1983–1985.
187.
Roufosse F, Schandene L, Sibille C, et al: Clonal Th2 lymphocytes in patients with the idiopathic hypereosinophilic syndrome. Br J Haematol 2000;109:540–548.
188.
Kitano K, Ichikawa N, Shimodaira S, et al: Eosinophilia associated with clonal T-cell proliferation. Leuk Lymphoma 1997;27:335–342.
189.
Roumier AS, Grardel N, Lai JL, et al: Hypereosinophilia with abnormal T cells, trisomy 7, and elevated TARC serum level. Haematologica 2003;88:ECR24.
190.
Bassan R, Locatelli G, Borleri G, Salvi A, Barbui T: Immunophenotypic evaluation of circulating T-cell clones in hypereosinophilic syndromes with or without abnormal CD3 and CD4 lymphocytes. Haematologica 2004;89:238–239.
191.
DeLavareille A, Roufosse F, Schmid-Grendelmeier P, et al: High serum thymus and activation-regulated chemokine levels in the lymphocytic variant of the hypereosinophilic syndrome. J Allergy Clin Immunol 2002;110:476–479.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.