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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158893 | GEO | 2021/06/21

REPOSITORIES: GEO

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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

The AP-1 -BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma

Project description:Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK– Anaplastic Large Cell Lymphoma (ALCL). Here we demonstrate high-level expression of BATF and BATF3 in ALCL, irrespective of the ALK-status. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements (AICE), differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs by CRISPR/Cas9 or siRNAs, or global AP-1 inhibition by the dominant-negative A-Fos results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17 / innate lymphoid cell type 3 (ILC3)-associated gene expression in ALCL, including marker genes such as AHR, IL17F, IL22, IL26, IL23R, IL18R1 and RORγt. Elevated IL-17A and IL-17F levels were detected in pretreatment sera of a subset of children and adolescents with ALK+ ALCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines, and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1 / BATFs for ALCL biology and lead to the concept that ALCL might originate from ILC3 cells.

2018-01-31 | GSE107951 | GEO

JAK dependent survival of ALK- ALCL

Project description:Activating JAK and STAT mutations were discovered in many T-cell malignancies including ALK- anaplastic large cell lymphomas (ALCL). However, such mutations often occur in a minority of patients. To investigate the clinical application of targeting Janus Kinase (JAK) for ALK- ALCL, we treated ALK- cell lines of different histologic origins with JAK inhibitors. Interestingly, most exogenous cytokine independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with STAT3 phosphorylation status of tumor cells. Employing retroviral shRNA knockdown, we demonstrated that these JAK inhibitor sensitive cells were dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some but not all JAK inhibitor sensitive cells. Moreover, the mutations alone could not explain the JAK1/STAT3 dependency as wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in select JAK inhibitor sensitive cells. High levels of cytokine expression including IL-6 were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest cytokine receptor signaling was required for tumor cell survival in diverse forms of ALK- ALCL even in the presence of JAK1/STAT3 mutations. Therefore, JAK-inhibitor therapy might benefit patients with ALK- ALCL that are pSTAT3+.

2017-08-22 | GSE96048 | GEO

Bach2 attenuates IL-2R signalling to control Treg homeostasis and Tfr development

Project description:Differentiation and homeostasis of Foxp3 + regulatory T cells (Tregs) are tightly controlled by the interleukin-2 receptor (IL-2R) signaling, yet the mechanisms governing these processes are incompletely understood. Here we report that transcription factor Bach2 attenuates IL-2R signaling to coordinate Treg differentiation and homeostasis by directly repressed CD25 (IL-2Rα). Thus, Bach2 balances IL-2R signaling to orchestrate development and homeostasis of various Treg subsets.

2021-05-11 | GSE164937 | 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

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

Project description: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.

2009-11-16 | GSE14879 | GEO

NPM-ALK expression levels identify two distinct signatures in Anaplastic Large Cell Lymphoma of Childhood

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

Identification of sites bound by c-Jun and JunB transcription factors in the Karpas 299 ALK+ ALCL cell line

Project description:In order to identify sites bound by c-Jun/JunB in ALK+ ALCL, we performed ChIP-Seq on the Karpas 299 ALK+ ALCL cell line.

2020-09-01 | GSE151413 | GEO

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

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

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