title: The hypereosinophilic syndrome: fluorescence in situ hybridization detects the del(4)(q12)-FIP1L1/PDGFRA but not genomic rearrangements of other tyrosine kinases.
abstract: OBJECTIVE
  According to WHO criteria, the idiopathic hypereosinophilic syndrome (HES) is defined as persistent eosinophilia (>1.5x10(9)/L) without underlying causes, which is associated with signs or symptoms of organ involvement. Increased bone marrow blasts (>5%) or cytogenetic/genetic markers indicate chronic eosinophilic leukemia (CEL). A cryptic deletion of 4q12, i.e. del(4)(q12), producing the FIP1L1/PDGFRA fusion gene, identifies a distinct CEL subgroup (4q-/CEL). Our aims were: a) to use interphase-fluorescent in situ hybridization (FISH) to detect the cryptic 4q12 deletion; b) to compare the clinico-hematologic features of 4q-/CEL with other HES; c) to investigate whether PDGFRB, FGFR1, ABL1, and ETV6-activated tyrosine kinases are rearranged in CEL/HES.
  
  
  METHODS
  This multicenter study included 20 patients fulfilling the WHO criteria for HES and 6 patients without signs/symptoms of end-organ involvement. Double-color FISH was applied in all cases to investigate del(4)(q12). Further interphase-FISH assessed whether PDGFRB/5q33, FGFR1/8p11, ABL1/9q34, and ETV6/12p13, undergo rearrangements in HES.
  
  
  RESULTS
  Ten of the 26 patients (9 males and 1 female) had a cryptic del(4)(q12)-FIP1L1/PDGFRA which was confirmed by reverse transcription polymerase chain reaction (RT-PCR) analysis in four. Hepatomegaly and splenomegaly were significantly more frequent in these 10 than in the other 16 patients. Seven of these 10 patients received imatinib mesylate therapy and all achieved hematologic remission. In 3 of the patients interphase-FISH and RT-PCR demonstrated cytogenetic and molecular remission. Improvements were observed in signs and symptoms of cardiac and central nervous system involvement in 2 and 1 patient, respectively. Rearrangements of PDGFRB, FGFR1, ABL1, or ETV6 were not detected in this study.
  
  
  CONCLUSIONS
  FISH is a reliable diagnostic test for differentiating 4q-/CEL from other forms of HES, allowing an early diagnosis of good responders to imatinib mesylate therapy. For the first time we show that PDGFRB, FGFR1, ABL1 and ETV6 are not rearranged in HES and 4q-/CEL cases we studied.
authors.affiliation: University of Perugia, Policlinico Monteluce, Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: La Starza
authors.forename: Giorgina
authors.initials: G
authors.lastname: Specchia
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
authors.forename: Donatella
authors.initials: D
authors.lastname: Beacci
authors.forename: Chiara
authors.initials: C
authors.lastname: Nozzoli
authors.forename: Luigiana
authors.initials: L
authors.lastname: Luciano
authors.forename: Anna
authors.initials: A
authors.lastname: Aventin
authors.forename: Constantina
authors.initials: C
authors.lastname: Sambani
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Testoni
authors.forename: Marco
authors.initials: M
authors.lastname: Foppoli
authors.forename: Rosangela
authors.initials: R
authors.lastname: Invernizzi
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D001854:Bone Marrow Cells / Q000648:ultrastructure; D002648:Child; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics* / Q000648:ultrastructure; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000201:enzymology / Q000235:genetics*; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics*; D009928:Organ Specificity; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D039221:mRNA Cleavage and Polyadenylation Factors / Q000032:analysis / Q000235:genetics*
chemical_list: D000305:Adrenal Cortex Hormones; D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha