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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 |
Type |
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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Address |
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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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 |
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no |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
42 |
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Author |
Pui, C.-H.; Relling, M.V.; Downing, J.R. |
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Title |
Acute lymphoblastic leukemia |
Type |
Journal Article |
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Year |
2004 |
Publication |
The New England Journal of Medicine |
Abbreviated Journal |
N Engl J Med |
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Volume |
350 |
Issue |
15 |
Pages |
1535-1548 |
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Keywords |
Age Factors; Genotype; Humans; Molecular Biology; Mutation; Pharmacogenetics; Polymorphism, Genetic; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics; Prognosis; Translocation, Genetic |
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Abstract |
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Address |
Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. ching-hon.pui@stjude.org |
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English |
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ISSN |
0028-4793 |
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WP6 In vivo |
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Notes |
PMID:15071128 |
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no |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
43 |
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Author |
Pui, C.-H.; Robison, L.L.; Look, A.T. |
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Title |
Acute lymphoblastic leukaemia |
Type |
Journal Article |
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Year |
2008 |
Publication |
Lancet |
Abbreviated Journal |
Lancet |
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Volume |
371 |
Issue |
9617 |
Pages |
1030-1043 |
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Keywords |
Adolescent; Adult; Age Factors; Antineoplastic Agents/*therapeutic use; Child; Child, Preschool; Disease-Free Survival; Humans; Pharmacogenetics; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/physiopathology; Randomized Controlled Trials as Topic; Risk Assessment; Translocation, Genetic/*genetics; Treatment Outcome |
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Abstract |
Acute lymphoblastic leukaemia, a malignant disorder of lymphoid progenitor cells, affects both children and adults, with peak prevalence between the ages of 2 and 5 years. Steady progress in development of effective treatments has led to a cure rate of more than 80% in children, creating opportunities for innovative approaches that would preserve past gains in leukaemia-free survival while reducing the toxic side-effects of current intensive regimens. Advances in our understanding of the pathobiology of acute lymphoblastic leukaemia, fuelled by emerging molecular technologies, suggest that drugs specifically targeting the genetic defects of leukaemic cells could revolutionise management of this disease. Meanwhile, studies are underway to ascertain the precise events that take place in the genesis of acute lymphoblastic leukaemia, to enhance the clinical application of known risk factors and antileukaemic agents, and to identify treatment regimens that might boost the generally low cure rates in adults and subgroups of children with high-risk leukaemia. |
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Address |
Department of Oncology, St Jude Children's Research Hospital and University of Tennessee Health Science Center, Memphis, TN 38105, USA. ching-hon.pui@stjude.org |
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English |
Summary Language |
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Abbreviated Series Title |
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Series Volume |
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Series Issue |
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ISSN |
0140-6736 |
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WP6 In vivo |
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Notes |
PMID:18358930 |
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Call Number |
CBM.UAM @ ccobaleda @ |
Serial |
44 |
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