Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T-ALL
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jules Meijerink
PROVIDER: E-GEOD-26713 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we used a systems biology approach, based on the reverse engineering of signaling regulatory networks, which identified the AKT1 kinase as a signaling factor driving glucocorticoid resistance in T-ALL. Indeed, activation of AKT1 in T-ALL lymphoblasts impairs glucocorticoid-induced apoptosis. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor NR3C1 protein at position S134 and blocks glucocorticoid-induced NR3C1 translocation to the nucleus. Consistently, inhibition of AKT1 with MK-2206 increases the response of T-ALL cells to glucocorticoid therapy both in T-ALL cell lines and in primary patient samples thus effectively reversing glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of ATK1 inhibitors and glucocorticoids, in combination, for the treatment of T-ALL. This study includes 228 T-ALL samples of which 117 samples are re-analysis of GSE26713.
2013-05-30 | E-GEOD-32215 | biostudies-arrayexpress
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner possibly delineating specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv(7)(p15q34) cases, is characterized by elevated expression of HOXA genes. Using a gene expression based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new cases with elevated HOXA levels. Using array-CGH, a cryptic and recurrent deletion, del(9)(q34.11q34.13), was exclusively identified in 3 of these 5 cases. This deletion results in a conserved SET-NUP214 fusion product, that was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it may interact with CRM1 and DOT1L leading to the transcriptional activation of HOXA genes. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. We combined gene expression profiling and array-CGH analysis to detect a new and recurrent molecular cytogenetic abnormality in T-ALL patients that co-clustered with 5 well-defined HOXA-activated T-ALL samples. We describe the cloning of a recurrent SET-NUP214 fusion product in these samples, and identified a potential mechanism by which SET-NUP214 may activate the HOXA gene cluster as potential leukemogenic event in T-ALL. Experiment Overall Design: For 67 T-ALL patients having one of the major molecular cytogenetic abnormalities (i.e. TAL1 (n=24), LMO2 (n=9), HOXA (n=5), HOX11/TLX1 (n=7), and HOX11L2/TLX3 (n=22)), differentially expressed probesets were calculated from Affymetrix U133plus2.0 data based upon a Wilcoxon analysis and corrected for multiple testing for each probeset. Significant and differentially expressed probesets were obtained for the TAL1, HOX11 and HOX11L2 subgroups. No significant probesets were obtained for the HOXA subgroup or the LMO2 subgroup . As TAL1 and LMO2 both participate in the same transcriptional complex, activation of these genes may both lead to a highly similar expression profile. Combined analysis of TAL1 and LMO2 rearranged cases revealed significant and differentially expressed probesets that, as expected, almost entirely overlapped with the gene signature obtained for the TAL1-subgroup only. Next, we clustered 92 T-ALL cases, that besides the 67 cases as described above further included 25 T-ALL that lacked any of these recurrent abnormalities. Cluster analysis was performed based upon the top 25, 50 or 100 most significant probesets for the TAL1, TAL1/LMO2, HOX11 and HOX11L2 subgroups combined with 15 HOXA probesets identified by Soulier et al (2005)
2008-04-07 | E-GEOD-10609 | biostudies-arrayexpress
Project description:To identify novel oncogenic pathways in T-cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular cytogenetic analyses including the Chromosome Conformation Capture on Chip (4C) method. Two T-ALL subtypes were identified that lacked rearrangements of known oncogenes. One subtype associated with cortical arrest, expression of cell cycle genes and ectopic NKX2-1 or NKX2-2 expression for which rearrangements were identified. The second subtype associated with immature T-cell development and high expression of the MEF2C transcription factor as consequence of rearrangements of MEF2C, transcription factors that target MEF2C or MEF2C-associated cofactors. We propose NKX2-1, NKX2-2 and MEF2C as T-ALL oncogenes that are activated by various rearrangements.
2011-04-11 | GSE26713 | GEO
Project description:In high income countries 90% of the patients achieve complete remission after induction chemotherapy. However, 30-40% of these patients suffer from relapse. These patients face a dismal prognosis, as the majority (>60%) of relapsed patients die within 5 years. As a result, outcome for pediatric acute myeloid leukemia (AML) patients remains poor and has stabilized over the past 15 years. To prevent or better treat relapse of AML is the best option to improve outcome. Despite patient specific differences, most patients do respond to initial therapy. This suggests that at relapse, mechanisms are active that cause the altered response to chemotherapy. Detailed understanding of mechanisms that cause relapse remain largely elusive. To gain insight in the molecular pathways that characterize relapsed AML, we performed genome wide gene expression profiling on paired initial diagnosis and relapsed AML samples of 23 pediatric AML patients. We used pathway analysis to find which molecular pathways are involved in altered gene expression between diagnosis and relapse samples of individual AML patients. 23 paired diagnosis and relapse bone marrow or peripheral blood samples were collected and cryo-preserved. They were later thawed and processed for hybridization to Affymetrix U133 Plus 2.0 arrays.
2015-05-07 | E-GEOD-52891 | biostudies-arrayexpress
Project description:The bHLH transcription factor stem cell leukemia gene (Scl) is a master regulator for hematopoiesis essential for hematopoietic specification and proper differentiation of the erythroid and megakaryocyte lineages. However, the critical downstream targets of Scl remain undefined. Here, we identified a novel Scl target gene, transcription factor myocyte enhancer factor 2 C (Mef2C) from Sclfl/fl fetal liver progenitor cell lines. Analysis of Mef2C-/- embryos showed that Mef2C, in contrast to Scl, is not essential for specification into primitive or definitive hematopoietic lineages. However, adult VavCre+Mef2Cfl/fl mice exhibited platelet defects similar to those observed in Scl deficient mice. The platelet counts were reduced, while platelet size was increased and the platelet shape and granularity was altered. Furthermore, megakaryopoiesis was severely impaired in vitro. ChIP-on-chip analysis revealed that Mef2C is directly regulated by Scl in megakaryocytic cells, but not in erythroid cells. In addition, an Scl independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice, characterized as severe age-dependent reduction of specific B cell progenitor populations reminiscent of premature aging. In summary, this work identifies Mef2C as an integral member of hematopoietic transcription factors with distinct upstream regulatory mechanisms and functional requirements in megakaryocyte and B-lymphoid lineages. Experiment Overall Design: Sclfl/fl hematopoietic progenitor lines were generated from fetal liver progenitors from E12.5 Sclfl/fl embryos9 by immortalization with Hox11 retrovirus.17 Sclfl/fl progenitor cells were cultured with IL3, and a clonal line containing cells with megakaryocyte morphology and acetylcholinesterase (AchE) activity was selected. The Sclfl/fl cell line was transduced with Cre- GFP retrovirus to generate the Scl Experiment Overall Design: Î?/Î? cell line, and the Scl Î?/Î? cell line was transduced with Scl retrovirus to re-introduce Scl expression (Scl Î?/Î? +Scl cell line). Megakaryocyte differentiation was enhanced by adding Tpo for 5 days before harvesting the cells. RNA was extracted with Trizol (Gibco BRL) and RNEasy (Qiagen) kits. Differential gene expression between Sclfl/fl, Scl Î?/Î? and Scl Î?/Î? +Scl cell lines was analyzed by Affymetrix MOE430_2 microarray in the microarray core facility at the Dana-Farber Cancer Institute.
2009-02-08 | E-GEOD-14478 | biostudies-arrayexpress
Project description:Childhood acute lymphoblastic leukemia (ALL) comprises a large group of genetic subtypes with a favorable prognosis characterized by a TEL-AML1-fusion, hyperdiploidy (>50 chromosomes) or E2A-PBX1 fusion and a smaller group with unfavorable outcome characterized by either a BCR-ABL-fusion, MLL-rearrangement or T-ALL. About 25% of precursor B-ALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. A double-loop cross validation was used to construct a classifier based on gene expression in ALL cells from 190 newly diagnosed cases (COALL cohort, GEO GSE13425) with a prediction accuracy of 90%. T-ALL, TEL-AML1-positive, hyperdiploid and E2A-rearranged cases were identified with 100% sensitivity and â?¥94% specificity. The classifier accuracy was confirmed in an independent cohort of 107 cases (87.9%, DCOG cohort, GEO GSE13351). Experiment Overall Design: Bone marrow and peripheral blood samples were collected at diagnosis and frozen. After thawing, RNA was extracted, labelled and hybridized to Affymetrix U133 Plus 2.0 arrays.
2009-02-01 | E-GEOD-13351 | biostudies-arrayexpress
Project description:Childhood acute lymphoblastic leukemia (ALL) comprises a large group of genetic subtypes with a favorable prognosis characterized by a TEL-AML1-fusion, hyperdiploidy (>50 chromosomes) or E2A-PBX1 fusion and a smaller group with unfavorable outcome characterized by either a BCR-ABL-fusion, MLL-rearrangement or T-ALL. About 25% of precursor B-ALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. A double-loop cross validation was used to construct a classifier based on gene expression in ALL cells from 190 newly diagnosed cases (COALL cohort, GEO GSE13425) with a prediction accuracy of 90%. T-ALL, TEL-AML1-positive, hyperdiploid and E2A-rearranged cases were identified with 100% sensitivity and â¥94% specificity. The classifier accuracy was confirmed in an independent cohort of 107 cases (87.9%, DCOG cohort, GEO GSE13351). Experiment Overall Design: 190 bone marrow and peripheral blood samples were collected at diagnosis and frozen. They were later thawed and hybridized to Affymetrix U133A arrays.
2009-01-31 | E-GEOD-13425 | biostudies-arrayexpress
Project description:We evaluated the role of TTF-1/NKX2-1 on Smad3 and Smad4 binding in lung cancer cell lines. Smad3 binding sites in A549 cells and Smad3, Smad4, and TTF-1/NKX2-1 binding sites in H441 cells were determined by ChIP-seq.
2014-07-27 | E-GEOD-51509 | biostudies-arrayexpress
Project description:Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving both JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
2021-11-02 | PXD017147 | Pride
Project description:Molecular cloning of a t(10;14)(q24;q32) from a B-cell lymphoma showed a recurrent breakpoint in homeobox NKX2-3 gene, which was highly expressed in comparison to non-expressing mature B lymphocytes. Epigenetically-mediated NKX2-3 over-expression was selectively found in patients with splenic marginal-zone lymphoma, MALT lymphoma and extranodal diffuse large-cell lymphoma. In young mice, restricted expression of NKX2-3 to lymphocytes activated multiple integrins (LFA-1, VLA-4, MAC-1), adhesion molecules (ICAM-1, MadCAM-1, L-selectin) and the chemokine receptor CXCR4 that enhanced their homing and migration to splenic tissues, whereby they were retained, progressively accumulating to form non-clonal tumors. At 18 months, B cells acquired genomic rearrangements and generated clonal B-cell lymphomas mirroring the spectrum of human NKX2-3-expressing tumors. Mouse and human lymphomas displaying NKX2-3 expression shared histopahological, genomic and molecular features, including canonical NF-KB activation. NF-KB inhibition reduced tumorigenecity of NKX2-3-positive lymphomas. Our study reveals that oncogenic NKX2-3 promotes B-cell lymphomagenesis by disturbing lymphocyte dynamics. Comparisson of global gene expression profiling between Emu-NKX2-3 transgenes mice and wild type mice.
2016-07-22 | E-GEOD-49356 | biostudies-arrayexpress