A case of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia with a rare FIP1L1 breakpoint.

Department of Human Genetics, Groupe Interdisciplinaire de Genoproteomique Appliquee, Centre Hospitalier Universitaire de Liège, University of Liège, Liège, Belgium.
Journal of Molecular Diagnostics (Impact Factor: 4.85). 08/2007; 9(3):414-9. DOI: 10.2353/jmoldx.2007.060196
Source: PubMed

ABSTRACT The idiopathic hypereosinophilic syndrome (HES) has remained for a long time a diagnosis of exclusion. Differential diagnosis between the HES and the related chronic eosinophilic leukemia (CEL) relied on the identification of signs of clonality that allowed, when present, the reclassification of patients as CEL. Recently, a new acquired mutation was described in approximately 50% of the HES/CEL patients: a cryptic deletion on chromosome band 4q12 generating a FIP1L1-PDGFRA fusion gene. According to the World Health Organization classification, this clonal abnormality has been proposed as a new surrogate marker for chronic eosinophilic leukemia diagnosis. Fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction protocols were developed for an accurate del(4)(q12q12) and FIP1L1-PDGFRA fusion gene detection. Here, we report a patient with a rare FIP1L1 intron 16 breakpoint located outside of the reported FIP1L1 breakpoint region (ie, from FIP1L1 introns 9 to 13). This case illustrates the risk of false-negative results with diagnostic procedures that do not take into account the occurrence of rare FIP1L1 breakpoints. As targeted therapy with tyrosine kinase inhibitors has dramatically changed the prognosis of FIP1L1-PDGFRA (+) CEL, false-negative results could hamper accurate diagnosis and treatment.

Download full-text


Available from: Frédéric Lambert, Mar 30, 2015
32 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data.
    Methods 01/2002; 25(4):402-8. DOI:10.1006/meth.2001.1262 · 3.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Before the 1990s, lack of evidence for a reactive cause of hypereosinophilia or chronic eosinophilic leukemia (e.g. presence of a clonal cytogenetic abnormality or increased blood or bone marrow blasts) resulted in diagnosticians characterizing such nebulous cases as 'idiopathic hypereosinophilic syndrome (HES)'. However, over the last decade, significant advances in our understanding of the molecular pathophysiology of eosinophilic disorders have shifted an increasing proportion of cases from this idiopathic HES 'pool' to genetically defined eosinophilic diseases with recurrent molecular abnormalities. The majority of these genetic lesions result in constitutively activated fusion tyrosine kinases, the phenotypic consequence of which is an eosinophilia-associated myeloid disorder. Most notable among these is the recent discovery of the cryptic FIP1L1-PDGFRA gene fusion in karyotypically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES, redefining these diseases as clonal eosinophilias. Rearrangements involving PDGFRA and PDGFRB in eosinophilic chronic myeloproliferative disorders, and of fibroblast growth factor receptor 1 (FGFR1) in the 8p11 stem cell myeloproliferative syndrome constitute additional examples of specific genetic alterations linked to clonal eosinophilia. The identification of populations of aberrant T-lymphocytes secreting eosinophilopoietic cytokines such as interleukin-5 establish a pathophysiologic basis for cases of lymphocyte-mediated hypereosinophilia. This recent revival in understanding the biologic basis of eosinophilic disorders has permitted more genetic specificity in the classification of these diseases, and has translated into successful therapeutic approaches with targeted agents such as imatinib mesylate and recombinant anti-IL-5 antibody.
    Bailli&egrave re s Best Practice and Research in Clinical Haematology 02/2006; 19(3):535-69. DOI:10.1016/j.beha.2005.07.013 · 2.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.
    Blood 05/2004; 103(8):2879-91. DOI:10.1182/blood-2003-06-1824 · 10.45 Impact Factor
Show more