Transcriptome profiling of T-lymphoblastic leukemia of childhood [gene expression]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE42038 | GEO | 2014/11/03
SECONDARY ACCESSION(S): PRJNA179034
REPOSITORIES: GEO
Similar Datasets
Project description:The purpose of this study was the principal investigation and frequency of RTK expression in primary T-ALLs. Primary initial T-ALLs were assessed regarding their transcriptome-wide expression profiles and screend for prominent RTK expression. Naive primary T-ALL samples were evaluated with regard to global mRNA expression and screened for prominent RTK expression. The dataset was used to investigate RTK expression frequencies in T-ALLs.
2014-11-03 | E-GEOD-42038 | biostudies-arrayexpress
Project description:Receptor tyrosine kinase (RTK)-dependent signaling has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) of childhood. However, the RTK-dependent signaling state and its interpretation with regard to biological behavior are often elusive. To decipher signaling circuits that link RTK activity with biological output in vivo, we established patient-derived xenograft ALL (PDX-ALL) models with dependencies on fms-like tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor β (PDGFRB), which were interrogated by phosphoproteomics using iTRAQ mass spectrometry. Signaling circuits were determined by receptor type and cellular context with few generic features, among which we identified group I p21-activated kinases (PAKs) as potential therapeutic targets. Growth factor stimulation markedly increased catalytic activities of PAK1 and PAK2. RNA interference (RNAi)-mediated or pharmacological inhibition of PAKs using allosteric or adenosine triphosphate (ATP)-competitive compounds attenuated cell growth and increased apoptosis in vitro. Notably, PAK1- or PAK2-directed RNAi enhanced the antiproliferative effects of the type III RTK and protein kinase C inhibitor midostaurin. Treatment of FLT3- or PDGFRB-dependent ALLs with ATP-competitive PAK inhibitors markedly decreased catalytic activities of both PAK isoforms. In FLT3-driven ALL, this effect was augmented by coadministration of midostaurin resulting in synergistic effects on growth inhibition and apoptosis. Finally, combined treatment of FLT3 D835H PDX-ALL with the ATP-competitive group I PAK inhibitor FRAX486 and midostaurin in vivo significantly prolonged leukemia progression-free survival compared with midostaurin monotherapy or control. Our study establishes PAKs as potential downstream targets in RTK-dependent ALL of childhood, the inhibition of which might help prevent the selection or acquisition of resistance mutations toward tyrosine kinase inhibitors.
2019-11-22 | PRD000749 | Pride
Project description:We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1x10-5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4x10-15, odds ratio[OR]=1.91; rs10994982, P=5.7x10-9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 x10-5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes. We used microarrays to detail the global program of gene expression in primary leukemic blasts cells from children diagnosed with acute lymphoblastic leukemia.
2009-08-16 | E-GEOD-17195 | biostudies-arrayexpress
Project description:Deregulated RTK activity has been implicated as a causal leukemogenic factor in the context of molecular aberrations that perturb differentiation in the hematopoietic lineage such as in childhood ALL. A deeper understanding of RTK signaling processes on a system-wide scale will be key in defining critical components of signaling networks. To link RTK activity with in vivo output in primary ALL we took a functional approach, which combined SH2 domain binding, mass spectrometry, and transcriptome analyses. Structure and composition of evolving networks were highly diverse with few generic features determined by receptor and cell type. A combinatorial assembly of varying context-dependent and few generic signaling components at multiple levels likely generates output specificity. PAK2 was identified as a phosphoregulated FLT3 target, whose allosteric inhibition resulted in apoptosis of ALL cells. Our studies provide evidence that a functional approach to leukemia signaling may yield valuable information for a network-directed intervention. Primary ALL samples were investigated on Affymetrix SNP 6.0 arrays for copy-number changes related to receptor tyrosine kinases (RTKs). Buffy-Coat samples of healthy persons were used as reference.
2014-11-03 | E-GEOD-42054 | biostudies-arrayexpress
Project description:Deregulated RTK activity has been implicated as a causal leukemogenic factor in the context of molecular aberrations that perturb differentiation in the hematopoietic lineage such as in childhood ALL. A deeper understanding of RTK signaling processes on a system-wide scale will be key in defining critical components of signaling networks. To link RTK activity with in vivo output in primary ALL we took a functional approach, which combined SH2 domain binding, mass spectrometry, and transcriptome analyses. Structure and composition of evolving networks were highly diverse with few generic features determined by receptor and cell type. A combinatorial assembly of varying context-dependent and few generic signaling components at multiple levels likely generates output specificity. PAK2 was identified as a phosphoregulated FLT3 target, whose allosteric inhibition resulted in apoptosis of ALL cells. Our studies provide evidence that a functional approach to leukemia signaling may yield valuable information for a network-directed intervention. Three different primary ALL samples expressing FLT3 and/or PDGFRß were stimulated with the corresponding ligands FLT3L and PDGF-BB for five time points. Unstimulated samples served as control. ALL22089 coexpresses FLT3 and PDGFRß. ALL109 expresses PDGFRß. ALL114 expresses FLT3.
2014-11-03 | E-GEOD-42001 | biostudies-arrayexpress
Project description:Although the 5-year survival of childhood Acute Lymphoblastic Leukemia (ALL) exceeds 80%, a group of patients presents poor prognosis due to early relapse. To date, treatment strategies are defined by cytogenetically-based subtype categorization. However, ALL patients without chromosomal translocations associated with poor prognosis lack diagnostic markers to adjust specific therapies. DNA methylation alteration is a frequent event in cancer with high potential in diagnosis, prognosis and prediction of drug response. Hence, we aimed to characterize childhood B-ALLs without Philadelphia (BCR-ABL) and MLL translocations based on their DNA methylation profile of more than 450,000 CpG sites to improve accuracy in prognosis and treatment strategies.
2012-11-07 | GSE39141 | GEO
Project description:We identified germline single nucleotide polymorphisms (SNPs) associated with childhood acute lymphoblastic leukemia (ALL) and its subtypes. Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed (P<1x10-5) between a pediatric ALL population (n=317) and non-ALL controls (n=17,958). Six of these SNPs differed (P≤0.05) in allele frequency among four ALL subtypes. Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P=1.4x10-15, odds ratio[OR]=1.91; rs10994982, P=5.7x10-9, OR=1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P=1.62 x10-5, OR=2.17; rs10994982, P=0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n=124 children with ALL) (P=0.003 and P=0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline genomic variations affect susceptibility to and characteristics of specific ALL subtypes.
2009-08-16 | GSE17195 | GEO
Project description:Despite decades of clinical use, mechanisms of glucocorticoid resistance are poorly understood. We treated primary murine T lineage acute lymphoblastic leukemias (T-ALLs) with the glucocorticoid dexamethasone (DEX) alone and in combination with the pan-PI3 kinase inhibitor GDC-0941 and observed a robust response to DEX that was modestly enhanced by GDC-0941. Continuous in vivo treatment invariably resulted in outgrowth of drug-resistant clones, ~30% of which showed markedly reduced glucocorticoid receptor (GR) protein expression. A similar proportion of relapsed human T-ALLs also exhibited low GR protein levels. De novo or pre-existing mutations in the gene encoding GR (Nr3c1) occurred in relapsed clones derived from multiple independent parental leukemias. CRISPR/Cas9 gene editing confirmed that loss of GR expression confers DEX resistance. Exposing drug-sensitive T-ALLs to DEX in vivo altered transcript levels of multiple genes, and this response was attenuated in relapsed T-ALLs. These data implicate reduced GR protein expression as a frequent cause of glucocorticoid resistance in T-ALL.
2019-12-13 | GSE141967 | GEO
Project description:Deregulated RTK activity has been implicated as a causal leukemogenic factor in the context of molecular aberrations that perturb differentiation in the hematopoietic lineage such as in childhood ALL. A deeper understanding of RTK signaling processes on a system-wide scale will be key in defining critical components of signaling networks. To link RTK activity with in vivo output in primary ALL we took a functional approach, which combined SH2 domain binding, mass spectrometry, and transcriptome analyses. Structure and composition of evolving networks were highly diverse with few generic features determined by receptor and cell type. A combinatorial assembly of varying context-dependent and few generic signaling components at multiple levels likely generates output specificity. PAK2 was identified as a phosphoregulated FLT3 target, whose allosteric inhibition resulted in apoptosis of ALL cells. Our studies provide evidence that a functional approach to leukemia signaling may yield valuable information for a network-directed intervention.
2014-11-03 | GSE42054 | GEO
Project description:Deregulated RTK activity has been implicated as a causal leukemogenic factor in the context of molecular aberrations that perturb differentiation in the hematopoietic lineage such as in childhood ALL. A deeper understanding of RTK signaling processes on a system-wide scale will be key in defining critical components of signaling networks. To link RTK activity with in vivo output in primary ALL we took a functional approach, which combined SH2 domain binding, mass spectrometry, and transcriptome analyses. Structure and composition of evolving networks were highly diverse with few generic features determined by receptor and cell type. A combinatorial assembly of varying context-dependent and few generic signaling components at multiple levels likely generates output specificity. PAK2 was identified as a phosphoregulated FLT3 target, whose allosteric inhibition resulted in apoptosis of ALL cells. Our studies provide evidence that a functional approach to leukemia signaling may yield valuable information for a network-directed intervention.
2014-11-03 | GSE42001 | GEO