Please use this identifier to cite or link to this item: https://doi.org/10.1182/blood-2009-07-235143
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dc.titleInterconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia
dc.contributor.authorSanda, T
dc.contributor.authorLi, X
dc.contributor.authorGutierrez, A
dc.contributor.authorAhn, Y
dc.contributor.authorNeuberg, D.S
dc.contributor.authorO'Neil, J
dc.contributor.authorStrack, P.R
dc.contributor.authorWinter, C.G
dc.contributor.authorWinter, S.S
dc.contributor.authorLarson, R.S
dc.contributor.authorVon Boehmer, H
dc.contributor.authorLook, A.T
dc.date.accessioned2020-11-23T09:00:51Z
dc.date.available2020-11-23T09:00:51Z
dc.date.issued2010
dc.identifier.citationSanda, T, Li, X, Gutierrez, A, Ahn, Y, Neuberg, D.S, O'Neil, J, Strack, P.R, Winter, C.G, Winter, S.S, Larson, R.S, Von Boehmer, H, Look, A.T (2010). Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia. Blood 115 (9) : 1735-1745. ScholarBank@NUS Repository. https://doi.org/10.1182/blood-2009-07-235143
dc.identifier.issn0006-4971
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/183915
dc.description.abstractTo identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for ?-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-?B and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells. © 2010 by The American Society of Hematology.
dc.publisherAmerican Society of Hematology
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceUnpaywall 20201031
dc.subjectalvespimycin
dc.subjectchaperone
dc.subjectgamma secretase inhibitor
dc.subjectheat shock protein 90
dc.subjectheat shock protein 90 inhibitor
dc.subjecthistone deacetylase
dc.subjectimmunoglobulin enhancer binding protein
dc.subjectMyc protein
dc.subjectNotch1 receptor
dc.subjectphosphatidylinositol 3 kinase
dc.subjectproteasome inhibitor
dc.subjectprotein kinase B
dc.subjecttumor suppressor protein
dc.subjectunclassified drug
dc.subjectenzyme inhibitor
dc.subjectNOTCH1 protein, human
dc.subjectNotch1 protein, mouse
dc.subjectsecretase
dc.subjectacute lymphoblastic leukemia
dc.subjectalgorithm
dc.subjectanalysis
dc.subjectanimal cell
dc.subjectanimal model
dc.subjectarticle
dc.subjectcancer growth
dc.subjectcancer inhibition
dc.subjectcell growth
dc.subjectcell survival
dc.subjectcomparative study
dc.subjectcontrolled study
dc.subjectdown regulation
dc.subjectdrug sensitivity
dc.subjectfemale
dc.subjectgene
dc.subjectgene expression
dc.subjecthuman
dc.subjecthuman cell
dc.subjectin vitro study
dc.subjectleukemia cell
dc.subjectleukemogenesis
dc.subjectmouse
dc.subjectnonhuman
dc.subjectnucleotide sequence
dc.subjectpathogenesis
dc.subjectprediction
dc.subjectpriority journal
dc.subjectsignal transduction
dc.subjectT lymphocyte
dc.subjectacute lymphoblastic leukemia
dc.subjectanimal
dc.subjectcell cycle
dc.subjectcell proliferation
dc.subjectcell transformation
dc.subjectdrug antagonism
dc.subjectexperimental leukemia
dc.subjectgene expression profiling
dc.subjectgenetics
dc.subjectmetabolism
dc.subjectoncogene myc
dc.subjectspecies difference
dc.subjecttumor cell line
dc.subjectAmyloid Precursor Protein Secretases
dc.subjectAnimals
dc.subjectCell Cycle
dc.subjectCell Line, Tumor
dc.subjectCell Proliferation
dc.subjectCell Survival
dc.subjectCell Transformation, Neoplastic
dc.subjectDown-Regulation
dc.subjectEnzyme Inhibitors
dc.subjectGene Expression Profiling
dc.subjectGenes, myc
dc.subjectHumans
dc.subjectLeukemia, Experimental
dc.subjectMice
dc.subjectPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma
dc.subjectReceptor, Notch1
dc.subjectSignal Transduction
dc.subjectSpecies Specificity
dc.typeArticle
dc.contributor.departmentMEDICINE
dc.description.doi10.1182/blood-2009-07-235143
dc.description.sourcetitleBlood
dc.description.volume115
dc.description.issue9
dc.description.page1735-1745
dc.published.statepublished
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