Methylation Analysis of ALK-positive pediatric Anaplastic Large Cell Lymphom
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PROVIDER: PRJNA774059 | ENA |
REPOSITORIES: ENA
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Project description:Anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma that accounts for 10–15% of all childhood lymphomas. Despite the observation that more than 90% of the cases show ALK-rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insight into the molecular heterogeneity within ALK-positive ALCL, we analyzed 46 ALK-positive ALCL samples by whole-exome sequencing, RNA-sequencing, and DNA methylation array analysis. Gene expression and methylation profiling consistently subclassified ALK-positive ALCL cases into two groups differentiated by ALK expression level. The ALK-low group showed enrichment pathways of the immune response and cytokine signaling and were more heavily hypermethylated than the ALK high group, which was characterized by enriched pathways of cell growth, proliferation, metabolic pathways, and large copy number change. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may be utilized as prognostic markers.
2023-01-02 | GSE186487 | GEO
Project description:Anaplastic Large Cell Lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2-5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the Anaplastic Lymphoma Kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-)ALCL subtypes, we performed a genome-wide DNA profiling using high density, single nucleotide polymorphism (SNP) arrays (SNP-array) on a series of 63 cases and seven cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an anti-apoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication. Genomic profiling of Anaplastic Large Cell Lymphoma
2013-09-20 | E-GEOD-50253 | biostudies-arrayexpress
Project description:Identification of transcriptional program influenced by the expression of lncRNA MAAT, a novel lncRNA highly expressed and strongly correlated with ALK-negative anaplastic large cell lymphomas. LncRNA MAAT was silenced through Antisense LNA GapmeRs strategy.
2024-12-13 | E-MTAB-12462 | biostudies-arrayexpress
Project description:Anaplastic large-cell lymphoma (ALCL) makes up approximately 15% of paediatric non-Hodgkin's lymphomas of childhood. The vast majority of them is associated with the t(2;5)(p23;q35) translocation that results in the expression of a hybrid oncogenic tyrosine kinase, NPM-ALK. In order to investigate ALCL biological characteristics we used transcriptional profiling approach. Genome-wide gene expression profiling, performed on 23 paediatric ALCL and 12 reactive lymph nodes specimens, showed two novel ALCL subgroups based on their NPM-ALK expression levels (named (ALK low and ALK high). Gene set enrichment analysis revealed, in ALK low samples, a positive enrichment of genes involved in the Interleukin signaling pathway, whereas we found increased expression of genes related to cell cycle progression and division in ALK high tumour samples, such as Aurora Kinase A (AURKA) and B (AURKB). Growth inhibition was observed upon administration of AURKA and AURKB inhibitors Alisertib and Barasertib and it was associated with perturbation of the cell cycle and induction of apoptosis. In conclusion we identified two novel ALCL subgroups, which display unique biological characteristics suggesting sensitivity to distinct targeted therapies.
2016-11-04 | GSE78513 | GEO
Project description:Structural genomic variants leading to anaplastic lymphoma kinase (ALK) gene fusions and aberrant expression of the ALK tyrosine kinase are the hallmark of subtypes of T- and B-lineage neoplasms, namely ALK-positive anaplastic large lymphoma (ALCL) and ALK-positive large B-cell lymphoma (LBCL). The latter is a rare aggressive lymphoma, which has been initially identified as a variant of diffuse LBCL (DLBCL) with plasmablastic features. Here, we performed comparative DNA methylation profiling of human and murine ALK-positive B-cell neoplasms. Array-based DNA methylation data from ALK-positive LBCL samples of eight patients were compared to that of DLBCL (n=75), multiple myeloma (MM, n=24), ALK-positive ALCL (n=12) and normal B-cell populations (n=93). ALK-positive LBCLs share a distinct DNA methylation signature similar to that of MM, characterized by lower global DNA methylation levels compared to DLBCLs and normal B-cell populations. DNA methylation alterations in ALK-positive LBCL were predominantly located in heterochromatic and polycomb-repressed regions. The epigenetic age and relative proliferative history of ALK-positive LBCL were intermediate between MM and DLBCL. B-cell neoplasms in NPM::ALK transgenic mice showed a similar hypomethylated signature when compared to normal murine B cells. Cross-species comparison indicated conservation of chromatin states and pathways affected by hypomethylation. Together, the findings suggest that in line with their phenotypical appearance human and murine ALK-positive B-cell lymphomas share an epigenetic profile more closely resembling that of plasma cell neoplasias than that of DLBCLs.
2025-09-10 | GSE289990 | GEO
Project description:Anaplastic Large Cell Lymphoma (ALCL) is a mature T-cell lymphoma that can present as a systemic or primary cutaneous disease. Systemic ALCL represents 2-5% of adult lymphoma but up to 30% of all pediatric cases. Two subtypes of systemic ALCL are currently recognized on the basis of the presence of a translocation involving the Anaplastic Lymphoma Kinase ALK gene. Despite considerable progress, several questions remain open regarding the pathogenesis of both ALCL subtypes. To investigate the molecular pathogenesis and to assess the relationship between the ALK(+) and ALK(-)ALCL subtypes, we performed a genome-wide DNA profiling using high density, single nucleotide polymorphism (SNP) arrays (SNP-array) on a series of 63 cases and seven cell lines. The commonest lesions were losses at 17p13 and at 6q21, encompassing the TP53 and PRDM1 genes respectively. The latter gene, coding for BLIMP1, was inactivated by multiple mechanisms, more frequently, but not exclusively, in ALK(-)ALCL. In vitro and in vivo experiments showed that that PRDM1 is a tumor suppressor gene in ALCL models, likely acting as an anti-apoptotic agent. Losses of TP53 and/or PRDM1 were present in 52% of ALK(-)ALCL, and in 29% of all ALCL cases with a clinical implication.
2013-09-20 | GSE50253 | GEO
Project description:Structural genomic variants leading to anaplastic lymphoma kinase (ALK) gene fusions and aberrant expression of the ALK tyrosine kinase are the hallmark of subtypes of T- and B-lineage neoplasms, namely ALK-positive anaplastic large lymphoma (ALCL) and ALK-positive large B-cell lymphoma (LBCL). The latter is a rare aggressive lymphoma, which has been initially identified as a variant of diffuse LBCL (DLBCL) with plasmablastic features. Here, we performed comparative DNA methylation profiling of human and murine ALK-positive B-cell neoplasms. Array-based DNA methylation data from ALK-positive LBCL samples of eight patients were compared to that of DLBCL (n=75), multiple myeloma (MM, n=24), ALK-positive ALCL (n=12) and normal B-cell populations (n=93). ALK-positive LBCLs share a distinct DNA methylation signature similar to that of MM, characterized by lower global DNA methylation levels compared to DLBCLs and normal B-cell populations. DNA methylation alterations in ALK-positive LBCL were predominantly located in heterochromatic and polycomb-repressed regions. The epigenetic age and relative proliferative history of ALK-positive LBCL were intermediate between MM and DLBCL. B-cell neoplasms in NPM::ALK transgenic mice showed a similar hypomethylated signature when compared to normal murine B cells. Cross-species comparison indicated conservation of chromatin states and pathways affected by hypomethylation. Together, the findings suggest that in line with their phenotypical appearance human and murine ALK-positive B-cell lymphomas share an epigenetic profile more closely resembling that of plasma cell neoplasias than that of DLBCLs.
2025-09-10 | GSE289988 | GEO
Project description:Structural genomic variants leading to anaplastic lymphoma kinase (ALK) gene fusions and aberrant expression of the ALK tyrosine kinase are the hallmark of subtypes of T- and B-lineage neoplasms, namely ALK-positive anaplastic large lymphoma (ALCL) and ALK-positive large B-cell lymphoma (LBCL). The latter is a rare aggressive lymphoma, which has been initially identified as a variant of diffuse LBCL (DLBCL) with plasmablastic features. Here, we performed comparative DNA methylation profiling of human and murine ALK-positive B-cell neoplasms. Array-based DNA methylation data from ALK-positive LBCL samples of eight patients were compared to that of DLBCL (n=75), multiple myeloma (MM, n=24), ALK-positive ALCL (n=12) and normal B-cell populations (n=93). ALK-positive LBCLs share a distinct DNA methylation signature similar to that of MM, characterized by lower global DNA methylation levels compared to DLBCLs and normal B-cell populations. DNA methylation alterations in ALK-positive LBCL were predominantly located in heterochromatic and polycomb-repressed regions. The epigenetic age and relative proliferative history of ALK-positive LBCL were intermediate between MM and DLBCL. B-cell neoplasms in NPM::ALK transgenic mice showed a similar hypomethylated signature when compared to normal murine B cells. Cross-species comparison indicated conservation of chromatin states and pathways affected by hypomethylation. Together, the findings suggest that in line with their phenotypical appearance human and murine ALK-positive B-cell lymphomas share an epigenetic profile more closely resembling that of plasma cell neoplasias than that of DLBCLs.
2025-09-10 | GSE289985 | GEO
Project description:Anaplastic Large Cell Lymphomas (ALCL) represent a subset of lymphomas in which the Anaplastic Lymphoma Kinase (ALK) gene is frequently fused to the NPM gene. We previously demonstrated that the constitutive phosphorylation of ALK chimeric proteins is sufficient to induce cellular transformation in vitro and in vivo, and that ALK activity is strictly required for the survival of ALK positive ALCL cells. To elucidate the signaling pathways required for ALK-mediated transformation and tumor maintenance, we analyzed the transcriptomes of multiple ALK positive ALCL cell lines abrogating their ALK-mediated signaling by inducible ALK RNA interference (RNAi) or with potent and cell permeable ALK inhibitors. Transcripts derived from the gene expression profiling (GEP) analysis uncovered a reproducible signature, which included a novel group of ALK-regulated genes. Functional RNAi screening on a set of these ALK transcriptional targets revealed that the transcription factor C/EBPb and the anti-apoptotic protein BCL2A1 are absolutely necessary to induce cell transformation and/or to sustain the growth and survival of ALK positive ALCL cells. Thus, we proved that an experimentally controlled and functionally validated GEP analysis represents a powerful tool to identify novel pathogenetic networks and validate biologically suitable target genes for therapeutic interventions. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of Anaplastic Large Cell Lymphoma (ALCL) cell lines (TS [a subclone of Sup-M2] and Su-DHL1) engineered to express ALK-A5 shRNA under a doxycycline-inducible promoter or treated with cell permeable pyrrolocarbazole-derived ALK inhibitors. A mutated ALK-A5M shRNA was used as control. Briefly, cells were transduced with pLV-DsRed-tTRKRAB, expanded, and used for transduction with pLVTH-GFP-shRNA lentiviral particles. Cells were induced with doxycycline (1 microg/ml) for 12 hours, double GFP+ DsRed+ cells selected by fluorescence-activated cell sorting. Cells expressing GFP in the absence of the inducer were removed by a second flow cytometry sorting, and expanded. shRNA expression was induced by doxycycline treatment for 72 or 84 hours. Drug treatments (300 nM), were performed in TS cells with ALK inhibitors (A2 or A3), mock compound (A1), or control diluent for 6 hours. 5 micrograms of total RNA was processed and hybridized to the Affymetrix HG-U133A chip following the manufacturer's instructions.
2008-06-14 | E-GEOD-6184 | biostudies-arrayexpress
Project description:Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T-cell lymphomas. Here, we investigated the effects of genetic or pharmacological HDAC inhibition on NPM-ALK positive anaplastic large cell lymphoma (ALCL) development to elucidate potential contraindications or indications for the use of HDACi for the treatment of this rare T-cell lymphoma. Short-term systemic pharmacological inhibition of HDACs using the class I-specific HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM-ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of highly homologous class I HDAC1 and HDAC2 enzymes were employed. In sharp contrast to the systemic inhibition, T cell-specific deletion of Hdac1 or Hdac2 in the ALCL mouse model significantly accelerated NPM-ALK-driven lymphomagenesis, with Hdac1 loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that Hdac1 deletion selectively perturbed cell type specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. The accelerated lymphomagenesis primarily depended on the enzymatic activity of HDAC1, as the expression of a catalytically inactive HDAC1 protein showed similar effects to the complete knockout. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development, however systemic pharmacological inhibition of HDACs is still a valid treatment strategy, which could potentially improve current therapeutic outcomes.
2025-06-16 | GSE271908 | GEO