140 research outputs found
Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13)
Recently, we and others reported a recurrent t(7;12)(q36;p13) found in
myeloid malignancies in children < or =18 months of age and associated
with a poor prognosis. Fluorescence in situ hybridization studies mapped
the 12p13 breakpoint to the first intron of ETV6 and narrowed down the
region of 7q36 involved. By using the sequences made public recently by
the Human Genome Project, two candidate genes in 7q36 were identified: the
homeobox gene HLXB9 and c7orf3, a gene with unknown function. Reverse
transcription-PCR of two cases with t(7;12), using primers for c7orf3 and
ETV6, was negative. However, reverse transcription-PCR for HLXB9-ETV6
demonstrated alternative splicing; the two major bands corresponded to
fusion of exon 1 of HLXB9 to exons 2 and 3, respectively, of ETV6. The
reciprocal ETV6-HLXB9 transcript was not detected. It remains to be
elucidated if the leukemic phenotype is attributable to the formation of
the HLXB9-ETV6 fusion protein, which includes the helix-loop-helix and E26
transformation-specific DNA binding domains of ETV6 or to the disruption
of the normal ETV6 protein
Prognostically useful gene-expression profiles in acute myeloid leukemia
BACKGROUND: In patients with acute myeloid leukemia (AML) a combination of
methods must be used to classify the disease, make therapeutic decisions,
and determine the prognosis. However, this combined approach provides
correct therapeutic and prognostic information in only 50 percent of
cases. METHODS: We determined the gene-expression profiles in samples of
peripheral blood or bone marrow from 285 patients with AML using
Affymetrix U133A GeneChips containing approximately 13,000 unique genes or
expression-signature tags. Data analyses were carried out with Omniviz,
significance analysis of microarrays, and prediction analysis of
microarrays software. Statistical analyses were performed to determine the
prognostic significance of cases of AML with specific molecular
signatures. RESULTS: Unsupervised cluster analyses identified 16 groups of
patients with AML on the basis of molecular signatures. We identified the
genes that defined these clusters and determined the minimal numbers of
genes needed to identify prognostically important clusters with a high
degree of accuracy. The clustering was driven by the presence of
chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular
genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We
identified several novel clusters, some consisting of specimens with
normal karyotypes. A unique cluster with a distinctive gene-expression
signature included cases of AML with a poor treatment outcome.
CONCLUSIONS: Gene-expression profiling allows a comprehensive
classification of AML that includes previously identified genetically
defined subgroups and a novel cluster with an adverse prognosis
Wide shear zones and the spot model: Implications from the split-bottom geometry
The spot model has been developed by Bazant and co-workers to describe
quasistatic granular flows. It assumes that granular flow is caused by the
opposing flow of so-called spots of excess free volume, with spots moving along
the slip lines of Mohr-Coulomb plasticity. The model is two-dimensional and has
been successfully applied to a number of different geometries. In this paper we
investigate whether the spot model in its simplest form can describe the wide
shear zones observed in experiments and simulations of a Couette cell with
split bottom. We give a general argument that is independent of the particular
description of the stresses, but which shows that the present formulation of
the spot model in which diffusion and drift terms are postulated to balance on
length scales of order of the spot diameter, i.e. of order 3-5 grain diameters,
is difficult to reconcile with the observed wide shear zones. We also discuss
the implications for the spot model of co-axiality of the stress and strain
rate tensors found in these wide shear flows, and point to possible extensions
of the model that might allow one to account for the existence of wide shear
zones.Comment: 6 pages, 6 figures, to be published in EPJ
Integrated genome-wide genotyping and gene expression profiling reveals BCL11B as a putative oncogene in acute myeloid leukemia with 14q32 aberrations
Acute myeloid leukemia is a neoplasm characterized by recurrent molecular aberrations traditionally demonstrated by cytogenetic analyses. We used high density genome-wide genotyping and gene expression profiling to reveal acquired cryptic abnormalities in acute myeloid leukemia. By genome-wide genotyping of 137 cases of primary acute myeloid leukemia, we disclosed a recurrent focal amplification on chromosome 14q32, which included the genes BCL11B, CCNK, C14orf177 and SETD3, in two cases. In the affected cases, the BCL11B gene showed consistently high mRNA expression, whereas the expression of the other genes was unperturbed. Flu
CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer
The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk
Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula
Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444-143839360)-(159119486-159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition
T(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: An international study of 62 patients
Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 World Health Organization classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study presents the clinical and genetic characteristics of 62 pediatric patients with t(6;9)/DEK-NUP214-rearranged myeloid leukemia; 54 diagnosed as having acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and eight as having myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relatively late onset (median age 10.4 years), male predominance (sex ratio 1.7), French-American-British M2 classification (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplantation in first complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% versus 18%; P<0.01) but not the overall survival (68% versus 54%; P=0.48). The presence of FLT3-ITD had a non-significant negative effect on 5-year overall survival compared with non-mutated cases (22% versus 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with a high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature
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