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  • 1
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    Molecular classification of cancer: class discovery and class prediction by gene expression monitoring (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-10-16
    Description: Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarrays is described and applied to human acute leukemias as a test case. A class discovery procedure automatically discovered the distinction between acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) without previous knowledge of these classes. An automatically derived class predictor was able to determine the class of new leukemia cases. The results demonstrate the feasibility of cancer classification based solely on gene expression monitoring and suggest a general strategy for discovering and predicting cancer classes for other types of cancer, independent of previous biological knowledge.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Golub, T R -- Slonim, D K -- Tamayo, P -- Huard, C -- Gaasenbeek, M -- Mesirov, J P -- Coller, H -- Loh, M L -- Downing, J R -- Caligiuri, M A -- Bloomfield, C D -- Lander, E S -- New York, N.Y. -- Science. 1999 Oct 15;286(5439):531-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, Cambridge, MA 02139, USA. golub@genome.wi.mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10521349" target="_blank"〉PubMed〈/a〉
    Keywords: Acute Disease ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cell Adhesion/genetics ; Cell Cycle/genetics ; *Gene Expression Profiling ; Homeodomain Proteins/genetics ; Humans ; Leukemia, Myeloid/*classification/drug therapy/*genetics ; Neoplasm Proteins/genetics ; Neoplasms/classification/genetics ; Oligonucleotide Array Sequence Analysis ; Oncogenes ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*classification/drug ; therapy/*genetics ; Predictive Value of Tests ; Reproducibility of Results ; Treatment Outcome
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-04-15
    Description: The Philadelphia chromosome, a chromosomal abnormality that encodes BCR-ABL1, is the defining lesion of chronic myelogenous leukaemia (CML) and a subset of acute lymphoblastic leukaemia (ALL). To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we performed a genome-wide analysis of diagnostic leukaemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CML cases. IKZF1 (encoding the transcription factor Ikaros) was deleted in 83.7% of BCR-ABL1 ALL, but not in chronic-phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG-mediated recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullighan, Charles G -- Miller, Christopher B -- Radtke, Ina -- Phillips, Letha A -- Dalton, James -- Ma, Jing -- White, Deborah -- Hughes, Timothy P -- Le Beau, Michelle M -- Pui, Ching-Hon -- Relling, Mary V -- Shurtleff, Sheila A -- Downing, James R -- England -- Nature. 2008 May 1;453(7191):110-4. doi: 10.1038/nature06866. Epub 2008 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18408710" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Child ; Fusion Proteins, bcr-abl/*genetics ; *Gene Deletion ; Humans ; Ikaros Transcription Factor/chemistry/*deficiency/*genetics/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*genetics/pathology ; Polymorphism, Single Nucleotide/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology ; Protein Isoforms/chemistry/genetics/metabolism ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-11-29
    Description: 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746051/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746051/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullighan, Charles G -- Phillips, Letha A -- Su, Xiaoping -- Ma, Jing -- Miller, Christopher B -- Shurtleff, Sheila A -- Downing, James R -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-30/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2008 Nov 28;322(5906):1377-80. doi: 10.1126/science.1164266.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19039135" target="_blank"〉PubMed〈/a〉
    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
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-01-21
    Description: Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Notta, Faiyaz -- Mullighan, Charles G -- Wang, Jean C Y -- Poeppl, Armando -- Doulatov, Sergei -- Phillips, Letha A -- Ma, Jing -- Minden, Mark D -- Downing, James R -- Dick, John E -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Jan 20;469(7330):362-7. doi: 10.1038/nature09733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto, Ontario M5G 1L7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248843" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Survival ; Clone Cells/*metabolism/*pathology ; Cyclin-Dependent Kinase Inhibitor p15/deficiency/genetics ; DNA Copy Number Variations/genetics ; Disease Progression ; *Evolution, Molecular ; Fusion Proteins, bcr-abl/*genetics ; Genes, p16 ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Models, Biological ; Neoplasm Transplantation ; Oligonucleotide Array Sequence Analysis ; Philadelphia Chromosome ; Polymorphism, Single Nucleotide/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/*pathology ; Survival Rate ; Transplantation, Heterologous
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    The genetic basis of early T-cell precursor acute lymphoblastic leukaemia (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-01-13
    Description: Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267575/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267575/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jinghui -- Ding, Li -- Holmfeldt, Linda -- Wu, Gang -- Heatley, Sue L -- Payne-Turner, Debbie -- Easton, John -- Chen, Xiang -- Wang, Jianmin -- Rusch, Michael -- Lu, Charles -- Chen, Shann-Ching -- Wei, Lei -- Collins-Underwood, J Racquel -- Ma, Jing -- Roberts, Kathryn G -- Pounds, Stanley B -- Ulyanov, Anatoly -- Becksfort, Jared -- Gupta, Pankaj -- Huether, Robert -- Kriwacki, Richard W -- Parker, Matthew -- McGoldrick, Daniel J -- Zhao, David -- Alford, Daniel -- Espy, Stephen -- Bobba, Kiran Chand -- Song, Guangchun -- Pei, Deqing -- Cheng, Cheng -- Roberts, Stefan -- Barbato, Michael I -- Campana, Dario -- Coustan-Smith, Elaine -- Shurtleff, Sheila A -- Raimondi, Susana C -- Kleppe, Maria -- Cools, Jan -- Shimano, Kristin A -- Hermiston, Michelle L -- Doulatov, Sergei -- Eppert, Kolja -- Laurenti, Elisa -- Notta, Faiyaz -- Dick, John E -- Basso, Giuseppe -- Hunger, Stephen P -- Loh, Mignon L -- Devidas, Meenakshi -- Wood, Brent -- Winter, Stuart -- Dunsmore, Kimberley P -- Fulton, Robert S -- Fulton, Lucinda L -- Hong, Xin -- Harris, Christopher C -- Dooling, David J -- Ochoa, Kerri -- Johnson, Kimberly J -- Obenauer, John C -- Evans, William E -- Pui, Ching-Hon -- Naeve, Clayton W -- Ley, Timothy J -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Mullighan, Charles G -- CA114766/CA/NCI NIH HHS/ -- CA98413/CA/NCI NIH HHS/ -- CA98543/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-33/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- U01GM92666/GM/NIGMS NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Jan 11;481(7380):157-63. doi: 10.1038/nature10725.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237106" target="_blank"〉PubMed〈/a〉
    Keywords: Age of Onset ; Child ; DNA Copy Number Variations/genetics ; Genes, ras/genetics ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; Genomics ; Hematopoiesis/genetics ; Histones/metabolism ; Humans ; Janus Kinases/genetics/metabolism ; Leukemia, Myeloid, Acute/drug therapy/genetics/pathology ; Molecular Sequence Data ; Mutation/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/*genetics/pathology ; Receptors, Interleukin-7/genetics ; Sequence Analysis, DNA ; Signal Transduction/genetics ; Stem Cells/metabolism/pathology ; T-Lymphocytes/metabolism/pathology ; Translocation, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    A novel retinoblastoma therapy from genomic and epigenetic analyses (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-01-13
    Description: Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289956/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289956/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jinghui -- Benavente, Claudia A -- McEvoy, Justina -- Flores-Otero, Jacqueline -- Ding, Li -- Chen, Xiang -- Ulyanov, Anatoly -- Wu, Gang -- Wilson, Matthew -- Wang, Jianmin -- Brennan, Rachel -- Rusch, Michael -- Manning, Amity L -- Ma, Jing -- Easton, John -- Shurtleff, Sheila -- Mullighan, Charles -- Pounds, Stanley -- Mukatira, Suraj -- Gupta, Pankaj -- Neale, Geoff -- Zhao, David -- Lu, Charles -- Fulton, Robert S -- Fulton, Lucinda L -- Hong, Xin -- Dooling, David J -- Ochoa, Kerri -- Naeve, Clayton -- Dyson, Nicholas J -- Mardis, Elaine R -- Bahrami, Armita -- Ellison, David -- Wilson, Richard K -- Downing, James R -- Dyer, Michael A -- CA21765/CA/NCI NIH HHS/ -- CA64402/CA/NCI NIH HHS/ -- EY014867/EY/NEI NIH HHS/ -- EY018599/EY/NEI NIH HHS/ -- GM81607/GM/NIGMS NIH HHS/ -- R01 CA155202/CA/NCI NIH HHS/ -- R01 EY014867/EY/NEI NIH HHS/ -- R01 EY014867-02/EY/NEI NIH HHS/ -- R01 EY018599/EY/NEI NIH HHS/ -- R01 EY018599-03/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 11;481(7381):329-34. doi: 10.1038/nature10733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computational Biology and Bioinformatics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22237022" target="_blank"〉PubMed〈/a〉
    Keywords: Aneuploidy ; Animals ; Cell Death/drug effects ; Cell Line ; Cell Survival/drug effects ; Chromosomal Instability/genetics ; Epigenesis, Genetic/*genetics ; Gene Expression Regulation, Neoplastic ; Genes, Retinoblastoma/genetics ; *Genomics ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/genetics/metabolism ; Mice ; *Molecular Targeted Therapy ; Mutation/genetics ; Protein Kinase Inhibitors/*pharmacology/therapeutic use ; Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/metabolism ; Retinoblastoma/*drug therapy/*genetics/pathology ; Retinoblastoma Protein/deficiency/genetics ; Sequence Analysis, DNA ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Loss of oncogenic Notch1 with resistance to a PI3K inhibitor in T-cell leukaemia (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-07-22
    Description: Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to gamma-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dail, Monique -- Wong, Jason -- Lawrence, Jessica -- O'Connor, Daniel -- Nakitandwe, Joy -- Chen, Shann-Ching -- Xu, Jin -- Lee, Leslie B -- Akagi, Keiko -- Li, Qing -- Aster, Jon C -- Pear, Warren S -- Downing, James R -- Sampath, Deepak -- Shannon, Kevin -- K08 CA134649/CA/NCI NIH HHS/ -- K99 CA157950/CA/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA180037/CA/NCI NIH HHS/ -- R37 CA072614/CA/NCI NIH HHS/ -- R37 CA72614/CA/NCI NIH HHS/ -- U01 CA084221/CA/NCI NIH HHS/ -- England -- Nature. 2014 Sep 25;513(7519):512-6. doi: 10.1038/nature13495. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA. ; Division of Haematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, Brigham &Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043004" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzamides/pharmacology/therapeutic use ; Clone Cells/drug effects/metabolism/pathology ; Diphenylamine/analogs & derivatives/pharmacology/therapeutic use ; Down-Regulation/drug effects ; *Drug Resistance, Neoplasm/drug effects/genetics ; Drug Synergism ; Genes, ras/genetics ; Indazoles/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/*antagonists & inhibitors ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug ; therapy/*genetics/metabolism/pathology ; Protein Kinase Inhibitors/*pharmacology/therapeutic use ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Notch1/chemistry/deficiency/genetics/*metabolism ; Signal Transduction/drug effects ; Sulfonamides/*pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    CREBBP mutations in relapsed acute lymphoblastic leukaemia (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-03-11
    Description: Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biological determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse. However, DNA sequence mutations in ALL have not been analysed in detail. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis-relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CREBBP, also known as CBP). The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076610/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076610/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullighan, Charles G -- Zhang, Jinghui -- Kasper, Lawryn H -- Lerach, Stephanie -- Payne-Turner, Debbie -- Phillips, Letha A -- Heatley, Sue L -- Holmfeldt, Linda -- Collins-Underwood, J Racquel -- Ma, Jing -- Buetow, Kenneth H -- Pui, Ching-Hon -- Baker, Sharyn D -- Brindle, Paul K -- Downing, James R -- DE018183/DE/NIDCR NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA021765-31/CA/NCI NIH HHS/ -- R21 DE018183/DE/NIDCR NIH HHS/ -- R21 DE018183-02/DE/NIDCR NIH HHS/ -- England -- Nature. 2011 Mar 10;471(7337):235-9. doi: 10.1038/nature09727.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390130" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; CREB-Binding Protein/chemistry/*genetics/metabolism ; Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Histone Acetyltransferases/genetics/metabolism ; Histones/metabolism ; Humans ; Mutation/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Protein Structure, Tertiary/genetics ; Recurrence
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    Novel mutations target distinct subgroups of medulloblastoma (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Robinson, Giles -- Parker, Matthew -- Kranenburg, Tanya A -- Lu, Charles -- Chen, Xiang -- Ding, Li -- Phoenix, Timothy N -- Hedlund, Erin -- Wei, Lei -- Zhu, Xiaoyan -- Chalhoub, Nader -- Baker, Suzanne J -- Huether, Robert -- Kriwacki, Richard -- Curley, Natasha -- Thiruvenkatam, Radhika -- Wang, Jianmin -- Wu, Gang -- Rusch, Michael -- Hong, Xin -- Becksfort, Jared -- Gupta, Pankaj -- Ma, Jing -- Easton, John -- Vadodaria, Bhavin -- Onar-Thomas, Arzu -- Lin, Tong -- Li, Shaoyi -- Pounds, Stanley -- Paugh, Steven -- Zhao, David -- Kawauchi, Daisuke -- Roussel, Martine F -- Finkelstein, David -- Ellison, David W -- Lau, Ching C -- Bouffet, Eric -- Hassall, Tim -- Gururangan, Sridharan -- Cohn, Richard -- Fulton, Robert S -- Fulton, Lucinda L -- Dooling, David J -- Ochoa, Kerri -- Gajjar, Amar -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Zhang, Jinghui -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):43-8. doi: 10.1038/nature11213.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722829" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CREB-Binding Protein/genetics ; Cadherins/genetics ; Cdh1 Proteins ; Cell Cycle Proteins/deficiency/genetics ; Cell Lineage ; Cerebellar Neoplasms/*classification/*genetics/pathology ; Child ; DEAD-box RNA Helicases/genetics ; DNA Copy Number Variations ; DNA Helicases/genetics ; DNA Mutational Analysis ; Disease Models, Animal ; Genome, Human/genetics ; Genomics ; Hedgehog Proteins/metabolism ; Histone Demethylases/genetics ; Histones/metabolism ; Humans ; Medulloblastoma/*classification/*genetics/pathology ; Methylation ; Mice ; Mutation/*genetics ; Nuclear Proteins/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Transcription Factors/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    PTEN action in leukaemia dictated by the tissue microenvironment (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-05-09
    Description: PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing. PTEN dephosphorylates phosphatidylinositol (3,4,5)-triphosphate, thereby opposing the activity of class I phosphatidylinositol 3-kinases that mediate growth- and survival-factor signalling through phosphatidylinositol 3-kinase effectors such as AKT and mTOR. To determine whether continued PTEN inactivation is required to maintain malignancy, here we generate an RNA interference-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal Pten knockdown in the haematopoietic compartment produced highly disseminated T-cell acute lymphoblastic leukaemia. Notably, reactivation of PTEN mainly reduced T-cell leukaemia dissemination but had little effect on tumour load in haematopoietic organs. Leukaemia infiltration into the intestine was dependent on CCR9 G-protein-coupled receptor signalling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, G-protein-coupled receptors may have an unanticipated role in driving tumour growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumour maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4165899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miething, Cornelius -- Scuoppo, Claudio -- Bosbach, Benedikt -- Appelmann, Iris -- Nakitandwe, Joy -- Ma, Jing -- Wu, Gang -- Lintault, Laura -- Auer, Martina -- Premsrirut, Prem K -- Teruya-Feldstein, Julie -- Hicks, James -- Benveniste, Helene -- Speicher, Michael R -- Downing, James R -- Lowe, Scott W -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA087497/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- S10 OD016282/OD/NIH HHS/ -- U01 CA105388/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 19;510(7505):402-6. doi: 10.1038/nature13239. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Department of Medicine I, Medical Center - University of Freiburg, 79106 Freiburg, Germany. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Howard Hughes Medical Institute, New York, New York 10065, USA. ; Institute of Human Genetics, Medical University of Graz, A-8010 Graz, Austria. ; Departments of Anesthesiology and Radiology, Stony Brook University, Stony Brook, New York 11794, USA. ; 1] Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [3] Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805236" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chemokines/metabolism ; Gene Knockdown Techniques ; Leukemia/*enzymology/genetics/*physiopathology ; Mice, Transgenic ; PTEN Phosphohydrolase/*genetics/*metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; RNA Interference ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Tumor Microenvironment/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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