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Author |
Mori, H.; Colman, S.M.; Xiao, Z.; Ford, A.M.; Healy, L.E.; Donaldson, C.; Hows, J.M.; Navarrete, C.; Greaves, M. |
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Title |
Chromosome translocations and covert leukemic clones are generated during normal fetal development |
Type |
Journal Article |
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Year |
2002 |
Publication |
Proceedings of the National Academy of Sciences of the United States of America |
Abbreviated Journal |
Proc Natl Acad Sci U S A |
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Volume |
99 |
Issue |
12 |
Pages |
8242-8247 |
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Keywords |
Base Sequence; Core Binding Factor Alpha 2 Subunit; DNA/blood; DNA Primers; *Embryonic and Fetal Development; Fetal Blood/chemistry; Humans; In Situ Hybridization, Fluorescence; Infant, Newborn; Leukemia/embryology/*genetics; Molecular Sequence Data; Oncogene Proteins, Fusion/*genetics; Polymerase Chain Reaction; RNA, Messenger/genetics; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors/*genetics; *Translocation, Genetic |
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Abstract |
Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia. |
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Address |
Leukaemia Research Fund Centre for Cell and Molecular Biology, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK |
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English |
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ISSN |
0027-8424 |
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WP6 In vivo |
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Notes |
PMID:12048236 |
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Call Number  |
CBM.UAM @ ccobaleda @ |
Serial |
38 |
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Author |
Mullighan, C.G.; Goorha, S.; Radtke, I.; Miller, C.B.; Coustan-Smith, E.; Dalton, J.D.; Girtman, K.; Mathew, S.; Ma, J.; Pounds, S.B.; Su, X.; Pui, C.-H.; Relling, M.V.; Evans, W.E.; Shurtleff, S.A.; Downing, J.R. |
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Title |
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia |
Type |
Journal Article |
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Year |
2007 |
Publication |
Nature |
Abbreviated Journal |
Nature |
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Volume |
446 |
Issue |
7137 |
Pages |
758-764 |
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Keywords |
Alleles; B-Cell-Specific Activator Protein/genetics; B-Lymphocytes/metabolism/pathology; Child; DNA-Binding Proteins/genetics; Gene Amplification/genetics; Genome, Human/*genetics; Genomics; Humans; Molecular Sequence Data; Mutation/*genetics; Point Mutation/genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology; Sequence Deletion/genetics; Trans-Activators/genetics; Translocation, Genetic/genetics |
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Abstract |
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. |
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Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA |
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ISSN |
0028-0836 |
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WP6 In vivo |
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Notes |
PMID:17344859 |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
39 |
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Author |
Mullighan, C.G.; Phillips, L.A.; Su, X.; Ma, J.; Miller, C.B.; Shurtleff, S.A.; Downing, J.R. |
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Title |
Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia |
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Journal Article |
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Year |
2008 |
Publication |
Science (New York, N.Y.) |
Abbreviated Journal |
Science |
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Volume |
322 |
Issue |
5906 |
Pages |
1377-1380 |
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Keywords |
B-Lymphocytes; Cell Cycle/genetics; Child; Cyclin-Dependent Kinase Inhibitor p15/genetics; Gene Deletion; *Gene Dosage; Genes, p16; *Genome, Human; Genomics; Humans; *Loss of Heterozygosity; Lymphopoiesis; Metabolic Networks and Pathways/genetics; *Mutation; Oligonucleotide Array Sequence Analysis; *Polymorphism, Single Nucleotide; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology; Proto-Oncogene Proteins c-ets/genetics; Recurrence; Repressor Proteins/genetics |
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Abstract |
Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for the minority of patients who relapse after treatment. To explore the genetic basis of relapse, we performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 pediatric patients with ALL. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs), with the CNAs acquired at relapse preferentially affecting genes implicated in cell cycle regulation and B cell development. Most relapse samples lacked some of the CNAs present at diagnosis, which suggests that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies revealed that cells corresponding to the relapse clone were often present as minor subpopulations at diagnosis. These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment, and they point to new targets for therapeutic intervention. |
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Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA |
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English |
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ISSN |
0036-8075 |
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WP6 In vivo |
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Notes |
PMID:19039135 |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
40 |
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Author |
Papaemmanuil, E.; Hosking, F.J.; Vijayakrishnan, J.; Price, A.; Olver, B.; Sheridan, E.; Kinsey, S.E.; Lightfoot, T.; Roman, E.; Irving, J.A.E.; Allan, J.M.; Tomlinson, I.P.; Taylor, M.; Greaves, M.; Houlston, R.S. |
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Title |
Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia |
Type |
Journal Article |
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Year |
2009 |
Publication |
Nature Genetics |
Abbreviated Journal |
Nat Genet |
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Volume |
41 |
Issue |
9 |
Pages |
1006-1010 |
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Keywords |
Alleles; Base Pairing; Base Sequence; CCAAT-Enhancer-Binding Proteins/genetics; Case-Control Studies; Child; Child, Preschool; *Chromosomes, Human, Pair 10; *Chromosomes, Human, Pair 14; *Chromosomes, Human, Pair 7; Confidence Intervals; DNA-Binding Proteins/genetics; Gene Frequency; *Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Genotype; Haplotypes; Humans; Ikaros Transcription Factor/genetics; Introns; Linkage Disequilibrium; Meta-Analysis as Topic; Molecular Sequence Data; Odds Ratio; Physical Chromosome Mapping; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*etiology/genetics; Probability; Recombination, Genetic; Risk Factors; Transcription Factors/genetics |
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Abstract |
To identify risk variants for childhood acute lymphoblastic leukemia (ALL), we conducted a genome-wide association study of two case-control series, analyzing the genotypes with respect to 291,423 tagging SNPs in a total of 907 ALL cases and 2,398 controls. We identified risk loci for ALL at 7p12.2 (IKZF1, rs4132601, odds ratio (OR) = 1.69, P = 1.20 x 10(-19)), 10q21.2 (ARID5B, rs7089424, OR = 1.65, P = 6.69 x 10(-19)) and 14q11.2 (CEBPE, rs2239633, OR = 1.34, P = 2.88 x 10(-7)). The 10q21.2 (ARID5B) risk association appears to be selective for the subset of B-cell precursor ALL with hyperdiploidy. These data show that common low-penetrance susceptibility alleles contribute to the risk of developing childhood ALL and provide new insight into disease causation of this specific hematological cancer. Notably, all three risk variants map to genes involved in transcriptional regulation and differentiation of B-cell progenitors. |
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Address |
Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK |
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English |
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ISSN |
1061-4036 |
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WP6 In vivo |
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Notes |
PMID:19684604 |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
41 |
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Author |
Perez-Caro, M.; Cobaleda, C.; Gonzalez-Herrero, I.; Vicente-Duenas, C.; Bermejo-Rodriguez, C.; Sanchez-Beato, M.; Orfao, A.; Pintado, B.; Flores, T.; Sanchez-Martin, M.; Jimenez, R.; Piris, M.A.; Sanchez-Garcia, I. |
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Title |
Cancer induction by restriction of oncogene expression to the stem cell compartment |
Type |
Journal Article |
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Year |
2009 |
Publication |
The EMBO Journal |
Abbreviated Journal |
EMBO J |
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Volume |
28 |
Issue |
1 |
Pages |
8-20 |
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Keywords |
Animals; *Gene Expression; Genes, abl/*genetics; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins/analysis; Nuclear Proteins/analysis; *Stem Cells; Survival Analysis |
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Abstract |
In human cancers, all cancerous cells carry the oncogenic genetic lesions. However, to elucidate whether cancer is a stem cell-driven tissue, we have developed a strategy to limit oncogene expression to the stem cell compartment in a transgenic mouse setting. Here, we focus on the effects of the BCR-ABLp210 oncogene, associated with chronic myeloid leukaemia (CML) in humans. We show that CML phenotype and biology can be established in mice by restricting BCR-ABLp210 expression to stem cell antigen 1 (Sca1)(+) cells. The course of the disease in Sca1-BCR-ABLp210 mice was not modified on STI571 treatment. However, BCR-ABLp210-induced CML is reversible through the unique elimination of the cancer stem cells (CSCs). Overall, our data show that oncogene expression in Sca1(+) cells is all that is required to fully reprogramme it, giving rise to a full-blown, oncogene-specified tumour with all its mature cellular diversity, and that elimination of the CSCs is enough to eradicate the whole tumour. |
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Address |
Experimental Therapeutics and Translational Oncology Program, Instituto de Biologia Molecular y Celular del Cancer, CSIC/Universidad de Salamanca, Salamanca, Spain |
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English |
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ISSN |
0261-4189 |
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WP6 In vivo |
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Notes |
PMID:19037256 |
Approved |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
42 |
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