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Gene expression study of anaplastic large cell lymphomas: cellular origin, pathogenesis and relation to Hodgkin lymphoma

ABSTRACT: Anaplastic large cell lymphoma (ALCL) is a main type of T cell lymphomas and comprises three distinct entities: systemic ALK+, systemic ALK- and cutaneous ALK- ALCL. Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK- ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of ALK+ and ALK- systemic ALCL, cutaneous ALCL and cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4+, CD8+ or CD30+ T cell origin. Indeed, ALCL display a general down-modulation of T cell characteristic molecules. All ALCL types show significant expression of NFκB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly few genes are differentially expressed between systemic and cutaneous ALK- ALCL despite their different clinical behaviour, and between ALK- ALCL and cHL despite their different cellular origin. ALK+ ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE14879 | GEO | 2009/11/16

SECONDARY ACCESSION(S): PRJNA111939

REPOSITORIES: GEO

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Genomic profiling of Anaplastic Large Cell Lymphoma

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

Genomic profiling of Anaplastic Large Cell Lymphoma

2013-09-20 | GSE50253 | GEO

ALK–transformed mature T lymphocytes restores early thymus progenitor features

Project description:Anaplastic large cell lymphoma (ALCL) is a mature T cell neoplasm that often expresses the CD4+ T cell surface marker. (It usually harbors the t(2;5) (p23;q35) translocation, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. We demonstrated that in vitro transduction of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant transformation. The tumor cells displayed morphological and immunophenotypical characteristics of primary patient–derived anaplastic large cell lymphomas. Cell growth, proliferation, and survival were strictly dependent on NPM-ALK activity and include activation of the key factors STAT3 and DNMT1 and expression of CD30 (the hallmark of anaplastic large-cell lymphoma). Implantation of NPM-ALK–transformed CD4+ T lymphocytes into immunodeficient mice resulted in the formation of tumors indistinguishable from patients’ anaplastic large cell lymphomas. Integration of “Omic” data revealed that NPM-ALK–transformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell precursors. Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OCT4, SOX2, and NANOG) and HIF2A, which is known to affect hematopoietic precursor differentiation and NPM-ALK+ cell growth. Altogether, for the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD30+ peripheral CD4+ T cells, in keeping with a thymic progenitor-like pattern.

2020-12-07 | GSE160123 | GEO

Transcription profiling of 32 human Anaplastic Large Cell Lymphomas (ALCL) and 5 ALCL cell lines to investigate differences between tumors expressing/not-expressing Anaplastic Lymphoma kinkase

Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Affymetrix UU133A gene expression data for a series of 32 cases of systemic Anaplastic Large Cell Lymphoma (ALCL) and 5 ALCL cell lines; used to (1) confirm that tumors expressing Anaplastic Lymphoma Kinase (ALK+ ALCL) and ALK- ALCLs are different entities, (2) identify most significantly differentially expressed genes between ALK+ and ALK- samples, (3) generate a molecular signature of ALK- ALCL, (4) perform unsupervised analysis classifying ALCL in sub-groups related to morphology and clinical variables (e.g. disease stage and enrichment with 'early relapse' patients). Principal Investigator: Dr Georges DELSOL-- Centre de Physiopathologie Toulouse-Purpan CHU-Purpan -- Toulouse -- France -- Email: delsol.g@chu-toulouse.fr Programme "Cartes d'identite des Tumeurs" (CIT) of the "Ligue Nationale Contre le Cancer" (LNCC) Submitter: Fabien PETEL (petelf@ligue-cancer.net)

2007-05-05 | E-TABM-117 | biostudies-arrayexpress

Identification of a new subclass of ALK negative ALCL expressing aberrant levels of ERBB4 transcripts

Project description:Anaplastic Large Cell Lymphoma (ALCL) is a clinical and biological heterogeneous disease including ALK positive and ALK negative systemic forms. To discover biomarkers and/or genes involved in ALK negative ALCL pathogenesis, we applied the Cancer Outlier Profile Analysis (COPA) algorithm to a gene expression profiling data set including 249 cases of T-NHLs and normal T-cells. Ectopic co-expression of ERBB4 and COL29A1 genes was detected in 24% of ALK negative ALCL patients. RNA sequencing and 5'RNA Ligase Mediated Rapid Amplification of cDNA Ends (RLM-RACE) identified two novel ERBB4 truncated transcripts, displaying intronic Transcription Starting Sites. ERBB4 expression was confirmed at protein level by western blotting and immunohistochemistry. Moreover, by luciferase assays we defined that the expression of ERBB4 aberrant transcripts is promoted by endogenous intronic Long Terminal Repeats (LTRs). In conclusion, we identified a new subclass of ALK negative ALCL characterized by aberrant expression of ERBB4 truncated transcripts carrying intronic 5'UTRs.

2015-10-22 | GSE65823 | GEO

Histone acetylation and DNA demethylation of T-cells result in an anaplastic large cell lymphoma-like phenotype.

Project description:A characteristic feature of anaplastic large cell lymphoma (ALCL) is the significant reduction of the T-cell expression program despite its T-cell origin, a finding very similar to the loss of B-cell identity of classical Hodgkin lymphoma (cHL). Previously we demonstrated that epigenetic mechanisms are active in cHL to induce this peculiar phenotype. The results show that combined DNA demethylation and histone acetylation of T-cell lines induce an almost complete extinction of the T-cell phenotype, including the down-regulation of essential T-cell receptor signalling pathway genes such as CD3, LCK and ZAP70, as well as an up-regulation of ALCL-characteristic genes. In contrast, combined DNA demethylation and histone acetylation of ALCL cells is not able to reconstitute their T-cell phenotype. This clearly demonstrates that similar epigenetic mechanisms are active in ALCL and cHL which are responsible for the extinction of their cell type characteristic phenotype. We subjected T-cell lymphoma/leukemia cell lines and ALCL cell lines (n=4, each) to epigenetic modifiers to evoke DNA demethylation and the histone acetylation. Global gene expression profiling (Affymetrix) was performed from treated and untreated cell lines which were evaluated by real-time RT-PCR and Western Blot analysis.

2012-08-19 | E-GEOD-26101 | biostudies-arrayexpress

Histone acetylation and DNA demethylation of T-cells result in an anaplastic large cell lymphoma-like phenotype.

2012-08-19 | GSE26101 | GEO

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma [ChIP-Seq]

Project description:Systemic anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma comprising ALK-positive (ALK+) and ALK-negative (ALK−) as well as breast implant-associated (BIA)-ALCL. The prognosis for ALCL, ALK− in particular is poor, and already in second line there is an unmet medical need for effective treatment options. To identify genes defining ALCL cell state and dependencies, we here started by an unbiased characterization of super-enhancer regions by genome-wide H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). We identified, in addition to known key regulators, the AP-1 transcription factor member BATF3 and IL-2 receptor (IL2R) components among the genes with most extensively H3K27-acetylated regulatory regions. Consistently, specific and high-level expression of the IL-2R subunits, IL-2Rα, IL-2Rβ and IL-2Rγ in ALCL correlate with BATF3 expression. Confirming a regulatory link, expression of IL-2R subunits decreases following BATF3 knockout, and BATF3 is recruited to AP-1 sites in IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate growth of ALCL cells and activate STAT1, STAT5 and ERK, but not STAT3. In line, strong IL-2Rα expression in ALCL patients is linked to more aggressive clinical presentation. Finally, we demonstrate highly efficient killing of ALCL cells by an IL-2Rα-targeting antibody-drug conjugate in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R module for ALCL biology and identify IL-2Rα as the target of a promising treatment strategy for ALCL.

2021-06-21 | GSE158915 | GEO

Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma [RNA-Seq]

2021-06-21 | GSE158893 | GEO

Methylation Analysis of ALK-positive pediatric Anaplastic Large Cell Lymphom

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

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