Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 alpha and beta (PDGFRalpha, PDGFRbeta), 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.
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PMID:Molecular classification and pathogenesis of eosinophilic disorders: 2005 update. 1599 22

The MLL gene, located within band 11q23, has been shown to be involved in translocations with a large variety of reciprocal sites in both lymphoid and myeloid leukemia and has also been shown to undergo submicroscopic self-fusion/partial duplication. We report 29 patients with cytogenetic evidence of 11q23 alteration, all of which demonstrate molecular cytogenetic evidence of amplification of the MLL gene by fluorescence in situ hybridization (FISH). In all MLL cases, the patients were clinically classified as having transforming myelodysplasia (RAEB/RAEBT) or AML. An additional patient with AML was found by 24-color and gene-specific FISH to have AML1 oncogene amplification. Four patients had been previously diagnosed with cancer and had received topoisomerase II targeted drug therapy which is known to be associated with fusion transcripts involving the MLL and AML1 genes. MLL amplification appeared in various forms: an atypical banded region that bridges from 11q23 into a dicentric chromosome, expanded regions emanating from band 11q23, chromosome 11 paint-positive rings with "spoke-like" MLL amplification, and expansion at sites other than chromosome 11 (including extra markers) in the absence of one of the 11 homologues. The fluorescence pattern in most cases suggests palindromic duplication with neighboring sequences in the long arm of chromosome 11. As opposed to MYCN amplification in hsrs (homogeneously staining regions) and double minutes in neuroblastoma, amplification of MLL in most cases occurred at the site of the gene. All of our patients rapidly developed refractory AML. The frequency and clinical correlations of MLL gene amplification in leukemia will need careful follow-up, since the frequently cryptic amplification described in these cases may not generally provoke confirmatory FISH studies. The reported MLL cases represented about 1% of the total abnormal MDS/AML cases over 8 years. A common cytogenetic profile of 5 q-, -17/17 p-, -18/18 q-, and a missing or abnormal chromosome 11, may help direct appropriate follow-up studies. The MLL and the AML1 oncogenes appear to be the only oncogenes amplified at the natural site of the gene. Both genes also show a high degree of diversity of pathogenic mechanisms of leukemia evolution, including numerous reciprocal fusion genes in transformation to either AML or ALL and gain of function amplification.
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PMID:Oncogene amplification in transforming myelodysplasia. 1602 82

We report a 30-month-old female with intrauterine growth retardation, postnatal failure to thrive, pancytopoenia and myelodysplasia with monosomy 7 in the marrow. The child succumbed to overwhelming sepsis, following a bone marrow transplant to facilitate chemotherapy for metastatic hepatoblastoma--a tumour that has not been previously reported in myelodysplasia syndromes. Cytogenetic, molecular and microarray analysis of peripheral blood, skin fibroblasts and bone marrow revealed unusual results, suggestive of somatic chromosome instability. A normal peripheral blood karyotype was documented in infancy. Monosomy 7 was found in the bone marrow. Molecular (microsatellite marker) results for a later peripheral blood specimen were suggestive of partial maternal isodisomy 7q, and this was supported by microarray data on single-nucleotide polymorphisms. Microarray data on gene copy number, collected for the same blood specimen, indicated cryptic mosaicism for the monosomy 7 cell line, with the monosomic line lacking the paternal copy. In fibroblasts, cytogenetic data showed mosaic partial trisomy for distal 7p.
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PMID:Chromosome 7 aberrations in a young girl with myelodysplasia and hepatoblastoma: an unusual association. 1631 99

Several different investigations and methodologies have provided data supporting a monoclonal origin of neoplasia. For example, the vast majority of neoplastic disorders are cytogenetically monoclonal. Occasionally, however, clones with unrelated karyotypic anomalies are found, as, for example, in approximately 2% of acute myeloid leukemias (AML), myelodysplastic syndromes (MDS), and chronic myeloproliferative disorders (CMD). Whether such a cytogenetic polyclonality represents a polyclonal origin or whether different clones share a submicroscopic primary change, indicating a monoclonal origin, remains to be elucidated. Our objective was to ascertain if cryptic aberrations can be found in cytogenetically polyclonal hematologic malignancies using multicolor fluorescence in situ hybridization (M-FISH). Fourteen AML, MDS, and CMD cases were investigated. In none of these was a cryptic aberration found, common to all subclones, although the karyotypes were revised in two AMLs and one MDS. Thus, all malignancies were still classified as polyclonal after the M-FISH analyses. Based on the present results, we conclude that M-FISH, in general, does not reveal primary cryptic aberrations supporting a monoclonal origin of cytogenetically polyclonal hematologic malignancies.
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PMID:Multicolor fluorescence in situ hybridization characterization of cytogenetically polyclonal hematologic malignancies. 1633 65

Although trisomy 8 as the sole chromosome aberration is the most common numerical abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), little is known about its pathogenetic effects. Considering that +8 is a frequent secondary change in AML/MDS, cryptic--possibly primary--genetic aberrations may occur in cases with trisomy 8 as the apparently single anomaly. However, no such hidden anomalies have been reported. We performed a high-resolution genome-wide array-based comparative genome hybridization (array CGH) analysis of 10 AML/MDS cases with isolated +8, utilizing a 32K bacterial artificial chromosome array set, providing >98% coverage of the genome with a resolution of 100 kb. Array CGH revealed intrachromosomal imbalances, not corresponding to known genomic copy number polymorphisms, in 4/10 cases, comprising nine duplications and hemizygous deletions ranging in size from 0.5 to 2.2 Mb. A 1.8 Mb deletion at 7p14.1, which had occurred prior to the +8, was identified in MDS transforming to AML. Furthermore, a deletion including ETV6 was present in one case. The remaining seven imbalances involved more than 40 genes. The present results show that cryptic genetic abnormalities are frequent in trisomy 8-positive AML/MDS cases and that +8 as the sole cytogenetic aberration is not always the primary genetic event.
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PMID:High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration. 1649 92

Fluorescence in situ hybridization and comparative genomic hybridization characterized 6p rearrangements in eight primary and in 10 secondary myeloid disorders (including one patient with Fanconi anemia) and found different molecular lesions in each group. In primary disorders, 6p abnormalities, isolated in six patients, were highly heterogeneous with different breakpoints along the 6p arm. Reciprocal translocations were found in seven. In the 10 patients with secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS), the short arm of chromosome 6 was involved in unbalanced translocations in 7. The other three patients showed full or partial trisomy of the 6p arm, that is, i(6)(p10) (one patient) and dup(6)(p) (two patients). In 5/7 patients with unbalanced translocations, DNA sequences were overrepresented at band 6p21 as either cryptic duplications (three patients) or cryptic low-copy gains (two patients). In the eight patients with cytogenetic or cryptic 6p gains, we identified a common overrepresented region extending for 5-6 megabases from the TNF gene to the ETV-7 gene. 6p abnormalities were isolated karyotype changes in four patients. Consequently, in secondary AML/MDS, we hypothesize that 6p gains are major pathogenetic events arising from acquired and/or congenital genomic instability.
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PMID:Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia. 1661 24

Myelodysplastic syndromes (MDS) are a group of heterogeneous stem cell disorders with different clinical behaviors and outcomes. Conventional cytogenetics (CC) studies have demonstrated that the majority of MDS patients harbor clonal chromosome defects. The probability of discovering a chromosomal abnormality has been increased by fluorescence in situ hybridization (FISH), which has revealed that about 15% of patients with a normal chromosome pattern on CC may instead present cryptic defects. Cytogenetic abnormalities, except for the interstitial long-arm deletion of chromosome 5 (5q-), are not specific for any French-American-British (FAB)/World Health Organization (WHO) MDS subtypes, demonstrate the clonality of the disease, and identify peculiar morphological entities, thus confirming clinical diagnosis. In addition, chromosome abnormalities are independent prognostic factors predicting overall survival and the likelihood of progression in acute myeloid leukemia.
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PMID:Clinical relevance of cytogenetics in myelodysplastic syndromes. 1726 83

In bone marrow cells of 33 patients with myelodysplastic syndrome and acute myeloid leukemia, structural rearrangements of chromosome 7 were found with conventional G-banding: 8 with deletions 7q and 25 with translocations. In 29 of the patients, complex karyotypes were confirmed using multicolor fluorescence in situ hybridization (mFISH). Commercial probes (Abbot Molecular) were used for 7q22, 7q31, and 7q35, the regions most frequently deleted in myeloid malignancies. In three cases without deletions, high-resolution multicolor banding (mBAND) for chromosome 7 revealed other aberrations. Five groups of chromosomal rearrangements were established: (a) deletion 7q as a sole aberration (2 cases), (b) deletion 7q and complex karyotypes (6 cases), (c) combined translocations and deletions of 7q (17 cases), (d) combined translocation and deletion 7p (5 cases), and (e) translocation of chromosomes 7 without deletion 7p or 7q (3 cases). Deletions of all three FISH-screened regions were the most frequent, with heterogeneous breakpoints. The region 7p13.2 approximately p15.2 was most commonly deleted. Most of the deletions were cryptic, not detectable with conventional cytogenetics. Aberrations of chromosome 7 are associated with a very poor outcome; survival time in our cohort was short (median 7 months).
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PMID:Structural aberrations of chromosome 7 revealed by a combination of molecular cytogenetic techniques in myeloid malignancies. 1728 64

Duplication of the long arm of chromosome 1 (1q) has been detected accompanied with other chromosome abnormalities in Myelodysplastic Syndromes (MDS). However, as a sole karyotypic change, it is rarely observed. We present here two patients affected of a MDS that showed a dup(1)(q21q32) as a sole cytogenetic change in their bone marrow cells. Complementary methodologies confirmed the duplication of chromosome 1q and, did not show additional cryptic chromosome abnormalities. One patient acquired a secondary trisomy 8 and the other one progressed toward an acute leukemia with no additional cytogenetic alterations.
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PMID:dup(1)(q21q32) as a sole cytogenetic event is associated to a leukemic transformation in myelodysplastic syndromes. 1750 81

Clonal hematopoiesis, observed in certain forms of marrow failure including aplastic anemia (AA), may be due to stem cell depletion. Alternatively, oligoclonality may be a result of recruitment of a preexisting defective clone, such as in paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplastic syndromes (MDS). In PNH, exogenous permissive factors may be required for dominance of the abnormal clone, while in MDS, stem cells undergo transformation steps leading to a growth advantage. Stem or multipotent progenitor cell involvement in PNH is evidenced by long-term persistence of a clonal defect and its presence in all blood cells. In MDS, some clonal aberrations may have a 'founder-effect' and additional defects are secondary. Metaphase cytogenetics measures the proportion of clonal cells within dividing progenitor but not mature cells. Owing to low resolution, lesions can be found in only approximately 50% of MDS patients. This shortcoming may be overcome by application of newer technologies such as comparative genomic hybridization and SNP array-based karyotyping (SNP-A). SNP-A facilitates identification of cryptic lesions in bone marrow failure patients with normal or abnormal cytogenetics and allows for detection of loss of heterozygosity as a result of uniparental disomy, a lesion frequently found in MDS.
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PMID:Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. 1755 86


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