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)

Acquired complete and partial deletions of chromosome 7 are associated with several malignancies. In acute myelogenous leukemia (AML) and preleukemic myelodysplasia (MDS), loss of chromosome 7 portends a poor clinical outcome. The identity of a classical leukemia suppressor gene, however, has been elusive. Previously, we defined a candidate suppressor locus of approximately 6 Mb in the 7q31 interval. Here we report an island of retention of heterozygosity within this interval in a case of monosomy 7. Allelotyping of AML cell lines revealed that ML3 and HEL cells, karyotypically diploid for chromosome 7, are hemizygous for all the 7q31 loci, implicating loss of the wild type and duplication of the remaining chromosome 7. Based on the completed genomic sequence of chromosome 7, we have generated a transcript map of the critical region of loss (between the D7S525 and D7S2502 loci). Notably, a recently characterized tumor suppressor gene, DOCK4, and an evolutionarily conserved zinc finger gene, ZNF277, localize to this interval, head to head, within <0.5 kb of each other. Thus, the reagents generated in this study will be valuable in elucidating the role of loss of 7q31 loci in the pathogenesis of AML.
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PMID:Finer delineation and transcript map of the 7q31 locus deleted in myeloid neoplasms. 1621 64

Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region.
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PMID:Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q. 2153 34