Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements
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PROVIDER: PRJNA484939 | ENA |
REPOSITORIES: ENA
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Project description:Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. While ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. Additionally, DUSP22-rearranged ALCLs minimally expressed PD-L1 compared to other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like, immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.
2018-08-08 | GSE118238 | GEO
Project description:Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas broadly segregated into ALK-positive and ALK-negative types. Although ALK-positive ALCLs consistently bear rearrangements of the ALK tyrosine kinase gene, ALK-negative ALCLs are clinically and genetically heterogeneous. About 30% of ALK-negative ALCLs have rearrangements of DUSP22 and have excellent long-term outcomes with standard therapy. To better understand this group of tumors, we evaluated their molecular signature using gene expression profiling. DUSP22-rearranged ALCLs belonged to a distinct subset of ALCLs that lacked expression of genes associated with JAK-STAT3 signaling, a pathway contributing to growth in the majority of ALCLs. Reverse-phase protein array and immunohistochemical studies confirmed the lack of activated STAT3 in DUSP22-rearranged ALCLs. DUSP22-rearranged ALCLs also overexpressed immunogenic cancer-testis antigen (CTA) genes and showed marked DNA hypomethylation by reduced representation bisulfate sequencing and DNA methylation arrays. Pharmacologic DNA demethylation in ALCL cells recapitulated the overexpression of CTAs and other DUSP22 signature genes. In addition, DUSP22-rearranged ALCLs minimally expressed PD-L1 compared with other ALCLs, but showed high expression of the costimulatory gene CD58 and HLA class II. Taken together, these findings indicate that DUSP22 rearrangements define a molecularly distinct subgroup of ALCLs, and that immunogenic cues related to antigenicity, costimulatory molecule expression, and inactivity of the PD-1/PD-L1 immune checkpoint likely contribute to their favorable prognosis. More aggressive ALCLs might be pharmacologically reprogrammed to a DUSP22-like immunogenic molecular signature through the use of demethylating agents and/or immune checkpoint inhibitors.
| S-EPMC6161771 | biostudies-literature
Project description:Systemic anaplastic large cell lymphomas (ALCLs) are classified into ALK-positive and ALK-negative types. We recently reported that ALK-negative ALCLs are genetically heterogenous. The largest subset, representing 30% of cases, had rearrangements of the DUSP22 locus. These cases had favorable outcomes similar to ALK-positive ALCL, and superior to other ALK-negative ALCLs. Here, we examined the morphologic features of these cases in more detail. First, we conducted blinded review of hematoxylin and eosin slides of 108 ALCLs from our previous study, scoring cases for the presence of 3 histologic patterns and 5 cell types. Cases then were unblinded and re-reviewed to understand these features further. DUSP22-rearranged ALCLs were more likely than other ALK-negative ALCLs to have so-called doughnut cells (23% vs. 5%; P=0.039), less likely to have pleomorphic cells (23% vs. 49%; P=0.042), and nearly always (95%) had areas with sheet-like growth (common pattern). To examine the reproducibility of these findings, we conducted blinded review of hematoxylin and eosin slides of 46 additional ALK-negative ALCLs using a 0 to 3 scoring system to predict likelihood of DUSP22 rearrangement, the results of which correlated strongly with subsequent findings by fluorescence in situ hybridization (P<0.0001). Although all ALCLs share certain morphologic features, ALCLs with DUSP22 rearrangements show significant differences from other ALK-negative ALCLs, typically showing sheets of hallmark cells with doughnut cells and few large pleomorphic cells. These morphologic findings and our previous outcome data suggest that ALK-positive ALCLs and DUSP22-rearranged ALCLs represent prototypical ALCLs, whereas ALCLs lacking rearrangements of both DUSP22 and ALK require further study.
| S-EPMC4834837 | biostudies-literature
Project description:Detection of immunogenic proteins remains an important task for life sciences as it nourishes the understanding of pathogenicity, illuminates new potential vaccine candidates and broadens the spectrum of biomarkers applicable in diagnostic tools. Traditionally, immunoscreenings of expression libraries via polyclonal sera on nitrocellulose membranes or screenings of whole proteome lysates in 2-D gel electrophoresis are performed. However, these methods feature some rather inconvenient disadvantages. Screening of expression libraries to expose novel antigens from bacteria often lead to an abundance of false positive signals owing to the high cross reactivity of polyclonal antibodies towards the proteins of the expression host. A method is presented that overcomes many disadvantages of the old procedures. We incorporated a fusion tag prior to our genes of interest and attached the expressed fusion proteins covalently on microarrays. This enhances the specific binding of the proteins compared to nitrocellulose. Thus, it helps to reduce the number of false positives significantly. It enables us to screen for immunogenic proteins in a shorter time, with more samples and statistical reliability. We validated our method by employing several known genes from Campylobacter jejuni NCTC 11168. Four of proteins that have previously been described as immunogenic have successfully been assessed immunogenic abilities with our method. One protein with no known immunogenic behaviour before suggested potential immunogenicity. The method presented offers a new approach for screening of bacterial expression libraries to illuminate novel proteins with immunogenic features. It could provide a powerful and attractive alternative to existing methods and help to detect and identify bacterial virulence factors, vaccine candidates and potential biomarkers. The overall study was done with five technical replicates. Ten proteins derived from Campylobacter jejuni were tested regarding their immunogenic potential. The ten proteins derived from Campylobacter jejuni were fusion proteins, i.e., N-terminal HaloTag fused to: Gene <--> Protein cjaA <--> putative amino-acid transporter periplasmic solute-binding protein hisJ <--> histidine-binding protein precursor pal <--> peptidoglycan associated lipoprotein flaC <--> flagellin flaA <--> flagellin peb1a <--> bifunctional adhesin/ABC transporter aspartate/glutamate-binding protein pyrC <--> dihydroorotase (EC:3.5.2.3) pseB <--> UDP-GlcNAc-specific C4,6 dehydratase/C5 epimerase gapA <--> glyceraldehyde 3-phosphate dehydrogenase (EC:1.2.1.12) argC <--> N-acetyl-gamma-glutamyl-phosphate reductase (EC:1.2.1.38)
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