Sait, S.N. et al. Double minute chromosomes in acute myeloid leukemia and myelodysplastic syndrome: identification of new amplification regions by fluorescence in situ hybridization and spectral karyotyping. Genes Chromosom. Cancer 34, 42-47
Double minute chromosomes (dmin) are small chromatin bodies consisting of genes amplified in an extrachromosomal location. dmins are uncommon in hematologic malignancies; they are seen primarily in acute myeloid leukemia, with amplification of the MYC oncogene or, less frequently, the MLL transcription factor. Nine patients with hematologic malignancies with dmin were seen at the Roswell Park Cancer Institute between 1985 and 2000; eight had acute myeloid leukemia and one a myelodysplastic syndrome. Fluorescence in situ hybridization (FISH) demonstrated MYC amplification on dmin in four patients, but MLL amplification was not seen. Spectral karyotyping showed that the dmin derived from chromosome 11 in one patient and from chromosome 19 in two others without MYC or MLL amplification; derivation from these chromosomes was confirmed by FISH with chromosome paint probes. The dmin of chromosome 11 origin hybridized to a bacterial artificial chromosome (BAC) RP11-112M22 that maps to 11q24.3 and is predicted to contain ETS1 and other markers, including D11S11351 and D11S4091. The dmin of chromosome 19 origin in one patient hybridized to BACs RP11-46I12 and RP11-110J19; in the other patient, these clones did not hybridize with the dmin, but were found to be amplified on a marker chromosome that was derived from chromosome 19 in that patient's cells. These BACs have been mapped to 19q12-19q13.1 and 19q11-19q13.1, respectively, and are predicted to contain the markers D19S409 and D19S919 and the gene for ubiquinol-cytochrome C reductase, Rieske iron-sulfur polypeptide1 (UQCRFS1). dmin originating from chromosome 19 have not been reported previously in hematologic malignancies.
"Gene amplification causes an increase in the gene copy number and, subsequently, elevates the expression of the amplified genes, which modify normal growth control and survival pathway. In this connection, C-myc was the most frequently amplified gene, but cases with mixed lineage leukemia (MLL) gene amplification have also been reported in the current literature. The semi conservative replication of Deoxyribonucleic acid (DNA) in dmin has been demonstrated to occur in both human and mouse cell line. "
[Show abstract][Hide abstract] ABSTRACT: Homogeneously staining regions (HSR) or double minute chromosomes (dmin) are autonomously replicating extra-chromosomal elements that are frequently associated with gene amplification in a variety of cancers. The diagnosis of leukemia patients was based on characterization of the leukemic cells obtained from bone marrow cytogenetics. This study report two cases, one with Acute Myeloblastic Leukemia without maturation (AML-M1), aged 23-year-old female, and the other with chronic myelogenous leukemia (CML)-blast crisis, a 28-year-old female associated with double minute chromosomes. Most cases of acute myeloid leukemia with dmin in the literature (including our cases) have been diagnosed as having acute myeloid leukemia.
Journal of research in medical sciences 04/2013; 18(4):363-365. · 0.65 Impact Factor
"Consistent with our study showing overexpression of RISP in breast tumors and other tumors, previous studies report genetic amplification of the UQCRFS1/RISP gene not only in breast but also in ovarian cancers and in leukemia –. UQCRFS1/RISP amplification was found to be in 12.8% of breast tumors examined by Ohashi et al.  and 13.6% ovarian cases reported by Kaneko et al. . Data presented in this study suggest a correlation between the mtOXPHOS defects with the severity of breast cancer in that the aggressive metastatic breast cancer cell line, MDA-MB-231, contained the most aberrations in mtOXPHOS activity. "
[Show abstract][Hide abstract] ABSTRACT: We measured the mitochondrial oxidative phosphorylation (mtOXPHOS) activities of all five complexes and determined the activity and gene expression in detail of the Complex III subunits in human breast cancer cell lines and primary tumors. Our analysis revealed dramatic differences in activity of complex III between normal and aggressive metastatic breast cancer cell lines. Determination of Complex III subunit gene expression identified over expression and co-regulation of UQCRFS1 (encoding RISP protein) and UQCRH (encoding Hinge protein) in 6 out of 9 human breast tumors. Analyses of UQCRFS1/RISP expression in additional matched normal and breast tumors demonstrated an over expression in 14 out of 40 (35%) breast tumors. UQCRFS1/RISP knockdown in breast tumor cell line led to decreased mitochondrial membrane potential as well as a decrease in matrigel invasion. Furthermore, reduced matrigel invasion was mediated by reduced ROS levels coinciding with decreased expression of NADPH oxidase 2, 3, 4 and 5 involved in ROS production. These studies provide direct evidence for contribution of impaired mtOXPHOS Complex III to breast tumorigenesis.
PLoS ONE 08/2011; 6(8):e23846. DOI:10.1371/journal.pone.0023846 · 3.23 Impact Factor
"Of particular interest is ST14, also known as matripase. The gene maps to amplicon 11qIII, which can be found amplified independently and even in higher copy numbers than MLL (Patient P14; Table 1 (Nacheva et al., 1993; Crossen et al., 1999; Sait et al., 2002; Martinez-Ramirez et al., 2004, 2005)). ST14 codes for a type II transmembrane serine protease, which is known to cleave and thereby activate hepatocyte/scattering factor (HGF) (Uhland, 2006), which is also among the top 100 up-regulated genes in cases with MLL amplification in our datasets. "
[Show abstract][Hide abstract] ABSTRACT: AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p, and 7q, older age and fast progression of the disease with extremely poor prognosis. MLL has been shown to be overexpressed in cases with 11q amplification. However, in most of the cases, the amplified region is not restricted to the MLL locus. In this study, we investigated 19 patients with AML/MDS and MLL gain/amplification. By means of array CGH performed in 12 patients, we were able to delineate the minimal deleted regions within 5q and 17p and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases were used to identify candidate genes within these regions. Notably, analysis of our data suggests a correlation of loss of 5q and 17p and expression of genes present in 11q23-25. Furthermore, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from several other types of AML.
Genes Chromosomes and Cancer 06/2009; 48(6):510-20. DOI:10.1002/gcc.20658 · 4.04 Impact Factor
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