ABSTRACT
Idiopathic hypereosinophilic syndrome (HES) characterized by unexplained and persistent hypereosinophilia is heterogeneous and comprises several entities: a myeloproliferative form where myeloid lineages are involved with the interstitial chromosome 4q12 deletion leading to fusion between FIP1L1 and PDGFRA genes, the latter acquiring increased tyrosine kinase activity. And a lymphocytic variant, where hypereosinophilia is secondary to a primitive T lymphoid disorder demonstrated by the presence of a circulating T-cell clone. We performed molecular characterization of HES in 35 patients with normal karyotype by conventional cytogenetic analysis. TCRgamma gene rearrangements suggesting T clonality were seen in 11 (31%) patients, and FIP1L1-PDGFRA by RT-PCR in six (17%) of 35 patients, who showed no evidence of T-cell clonality. An elevated serum tryptase level was observed in FIP1L1-PDGFRA-positive patients responding to imatinib, whereas serum IL-5 levels were not elevated in T-cell associated hypereosinophilia. Sequencing FIP1L1-PDGFRA revealed scattered breakpoints in FIP1L1-exons (10-13), whereas breakpoints were restricted to exon 12 of PDGFRA. In the 29 patients without FIP1L1-PDGFRA, no activating mutation of PDGFRA/PDGFRB was detected; however; one patient responded to imatinib. FISH analysis of the 4q12 deletion was concordant with FIP1L1-PDGFRA RT-PCR data. Further investigation of the nature of FIP1L1-PDGFRA affected cells will improve the classification of HES.
Subject(s)
Chromosome Deletion , Cytogenetic Analysis , Hypereosinophilic Syndrome/diagnosis , Hypereosinophilic Syndrome/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Base Sequence , Benzamides , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 4/genetics , Exons , Female , France , Humans , Hypereosinophilic Syndrome/drug therapy , Imatinib Mesylate , In Situ Hybridization, Fluorescence/methods , Interleukin-5/blood , Male , Middle Aged , Molecular Sequence Data , Piperazines/administration & dosage , Piperazines/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/therapeutic use , Sequence Analysis, DNA , Serine Endopeptidases/blood , TryptasesSubject(s)
Cell Separation/methods , In Situ Hybridization, Fluorescence/methods , Neoplasm, Residual/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Adult , Antigens, CD34/blood , Cytogenetic Analysis , Disease-Free Survival , Humans , In Situ Hybridization, Fluorescence/standards , Neoplasm, Residual/genetics , Neoplasm, Residual/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Reverse Transcriptase Polymerase Chain Reaction/standards , Sensitivity and SpecificityABSTRACT
We report on the fusion of the monocytic leukemia zinc finger protein (MOZ) gene to the adenoviral E1A-associated protein p300 (p300) gene in acute monocytic leukemia M5 associated with a t(8;22)(p11;q13) translocation. We studied two patients with double-color fluorescence in situ hybridization (FISH) using the yeast artificial chromosome 176C9 and the bacterial artificial chromosome clone H59D10 specific to the MOZ and p300 genes, respectively. Both probes were split in the patients' chromosome metaphase cells, and the two derivative chromosomes were each labeled with both probes. We showed by Southern blot the rearrangement of the MOZ gene, and cloned the fusion transcripts in one patient carrying the t(8;22) by reverse transcription-polymerase chain reaction using MOZ- and p300-specific primers. Both fusion transcripts were expressed. This result defines a novel reciprocal translocation involving two acetyltransferases, MOZ and p300, resulting in an abnormal transcriptional co-activator that could play a critical role in leukemogenesis.
