Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A total of 1,921 leukapheresis procedures have been performed on 532 normal and CML donors at six research institutions, for the purpose of supporting granulocytopenic leukemia patients during infectious episodes. The addition of HES alone or in combination with either etiocholanolone or dexamethasone, resulted in a significant increase in the numbers of leukocytes (granulocytes) harvested by continuous and noncontinuous flow centrifugation. Normal donors participating in these programs were monitored prior to and immediately following each procedure by standard laboratory methods which revealed no serious or abnormal changes occurring as a result of the procedure in those undergoing single or multiple donations with these agents. CML donors tolerated the addition of only HES well, as evidenced by the lack of toxic reactions in three donors undergoing 101 to 121 procedures.
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PMID:Hydroxyethyl starch as an experimental adjunct to leukocyte separation by centrifugal means: review of safety and efficacy. 5 17

Hypereosinophilic syndromes may result either from eosinophilic differentiation of a clone of neoplastic cells or from reactive eosinophilia. In other patients HES is idiopathic. It appears likely that in many patients the "idiopathic' hypereosinophilic syndrome is actually a chronic myeloproliferative disorder. Those cases showing an increase of blast cells or a demonstrable clonal cytogenetic abnormality should be classified as eosinophilic leukaemia. In other cases the neoplastic nature of the disease can be recognized only in retrospect when a granulocytic sarcoma or AMI, develops. A few cases of idiopathic HES are consequent on cytokine secretion whereas others remain idiopathic at the time of death. When eosinophilia occurs as a feature of an acute or chronic myeloid leukaemia or a chronic myeloproliferative disorder the eosinophils are usually part of the leukaemic clone. However, eosinophilia in association with acute lymphoblastic leukaemia is usually reactive. Rare cases have a biphenotypic leukaemia/lymphoma with both eosinophils and lymphoid cells arising from a mutant pluripotent stem cell.
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PMID:Eosinophilic leukaemias and the idiopathic hypereosinophilic syndrome. 885 31

We recently identified the chimeric kinase FIP1L1-platelet-derived growth factor receptor alpha (PDGFRalpha) as a cause of the hypereosinophilic syndrome and of chronic eosinophilic leukemia. To investigate the role of FIP1L1-PDGFRA in the pathogenesis of acute leukemia, we screened 87 leukemia cell lines for the presence of FIP1L1-PDGFRA. One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion. Three structurally divergent kinase inhibitors--imatinib (STI-571), PKC412, and SU5614--inhibited the growth of EOL-1 cells. These results indicate that the fusion of FIP1L1 to PDGFRA occurs rarely in leukemia cell lines, but they identify EOL-1 as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and for the analysis of small molecule inhibitors of FIP1L1-PDGFRalpha.
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PMID:The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. 1463 Jul 92

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.
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PMID:Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. 1530 31

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.
Leukemia 2004 Apr
PMID:Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. 1497 4

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.
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PMID:Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. 1475 33

Chronic eosinophilic leukemia is a neoplastic condition with persistent eosinophilia as the major hematological abnormality and with the eosinophils being part of the neoplastic clone. Some cases can be recognized by traditional hematological criteria, but many can be recognized only when a clonal cytogenetic or molecular genetic abnormality is demonstrated. A range of cytogenetic and molecular genetic abnormalities has been recognized, including both those seen in other myeloid malignancies (such as trisomy 8, monosomy 7, and 20q-) and those that are particularly linked to eosinophil differentiation (such as rearrangements of PDGFRB, FGFR1, and PDGFRA, the latter with formation of a FIP1L1-PDGFRA fusion gene). The discovery of the FIP1L1-PDGFRA fusion gene has led to the recognition that many patients who would previously have been regarded as having idiopathic hypereosinophilia actually have chronic eosinophilic leukemia. The same fusion gene has also been found in patients with hypereosinophilia and atypical bone marrow mast cells but whether this syndrome should be regarded as a variant of eosinophilic leukemia or as a variant of systemic mastocytosis remains to be established.
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PMID:Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. 1530 12

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.
Leukemia 2005 May
PMID:Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. 1577 98

Chronic myeloproliferative diseases (CMPDs) are characterized by the abnormal proliferation and survival of one or more myeloid cell types. The archetype of this class of hematological diseases is chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia (Ph) chromosome, the result of t(9;22)(q34;q11), and the associated BCR-ABL1 oncogene. Some of the Ph-negative myeloproliferative diseases are characterized by other chromosomal translocations involving a variety of tyrosine kinase genes, including ABL1, ABL2, PDGFRA, PDGFRB, FGFR1, and JAK2. The majority of Ph-negative CMPDs, however, such as chronic eosinophilic leukemia, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are not characterized by the presence of recurrent chromosomal abnormalities. Recent studies have identified the FIP1L1-PDGFRA fusion gene, generated due to a small cryptic deletion on chromosome 4q12, and the activating V617F mutation in JAK2 in a significant fraction of Ph-negative CMPDs. These results show that abnormalities in tyrosine kinase genes are central to the molecular pathogenesis of CMPDs. Genome-wide screenings to identify novel tyrosine kinase abnormalities in CMPDs may contribute to further improvement of the diagnosis and the treatment of these diseases.
Leukemia 2006 Feb
PMID:Chronic myeloproliferative disorders: a tyrosine kinase tale. 1634 Oct 34

Idiopathic hypereosinophilic syndrome is a largely heterogeneous disorder defined as persistent, marked hypereosinophilia of unknown origin complicated by end-organ damage. Recent research in cellular and molecular biology has led to the characterization of distinct underlying hematological disorders, primitively involving cells of the myeloid or lymphoid lineage. The ability to classify many hypereosinophilic syndrome patients on the basis of pathogenesis of hypereosinophilia has radically changed therapeutic perspectives. Indeed, imatinib mesylate has become first-line therapy for patients in whom the FIP1L1-PDGFRalpha fusion gene is detected, whereas corticosteroids remain the mainstay for management of patients in whom hypereosinophilia is secondary to the overproduction of interleukin 5 by abnormal T-cells. Use of monoclonal anti-interleukin-5 antibodies in the latter group of patients has a strong rationale and could decrease cumulative corticosteroid doses and toxicity. As far as prognosis of these disease variants is concerned, hypereosinophilic syndrome patients with the FIP1L1-PDGFRalpha fusion gene may develop acute myelogenous (eosinophilic) leukemia, whereas those with clonal interleukin-5-producing T-cells have an increased risk of developing T-cell lymphoma. It is currently unclear whether timely therapeutic intervention in such patients could interfere with long-term progression toward malignant hematological disorders.
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PMID:Hypereosinophilic syndrome: lymphoproliferative and myeloproliferative variants. 1661 67


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