Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22208 | GEO | 2010/10/07
SECONDARY ACCESSION(S): PRJNA128875
REPOSITORIES: GEO
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Project description:We integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. DNA copy number alterations were defined in DLBCL and HL cell lines, normalized to healthy donors, by GISTIC analysis of Affymetrix SNP 6.0 single nucleotide polymorphism microarray data. Using this analysis, we identified 9p24 amplification to be over-represented in HL cell lines compared to DLBCL cell lines.
2010-10-06 | E-GEOD-22208 | biostudies-arrayexpress
Project description:Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.
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Project description:Nodular sclerosing Hodgkin lymphoma (NSHL) is a distinct, highly heritable Hodgkin lymphoma subtype. We undertook a genome-wide meta-analysis of 393 European-origin adolescent/young adult NSHL patients and 3315 controls using the Illumina Human610-Quad Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We identified 3 single nucleotide polymorphisms (SNPs) on chromosome 6p21.32 that were significantly associated with NSHL risk: rs9268542 (P = 5.35 × 10(-10)), rs204999 (P = 1.44 × 10(-9)), and rs2858870 (P = 1.69 × 10(-8)). We also confirmed a previously reported association in the same region, rs6903608 (P = 3.52 × 10(-10)). rs204999 and rs2858870 were weakly correlated (r(2) = 0.257), and the remaining pairs of SNPs were not correlated (r(2) < 0.1). In an independent set of 113 NSHL cases and 214 controls, 2 SNPs were significantly associated with NSHL and a third showed a comparable odds ratio (OR). These SNPs are found on 2 haplotypes associated with NSHL risk (rs204999-rs9268528-rs9268542-rs6903608-rs2858870; AGGCT, OR = 1.7, P = 1.71 × 10(-6); GAATC, OR = 0.4, P = 1.16 × 10(-4)). All individuals with the GAATC haplotype also carried the HLA class II DRB1*0701 allele. In a separate analysis, the DRB1*0701 allele was associated with a decreased risk of NSHL (OR = 0.5, 95% confidence interval = 0.4, 0.7). These data support the importance of the HLA class II region in NSHL etiology.
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Project description:Comparative proteome analysis of HL and DLBCL educated human macrophages by SWATH-MS.
2020-01-29 | PXD016128 | Pride
Project description:PURPOSE:Classical Hodgkin lymphoma (cHL) and primary mediastinal large B-cell lymphoma (MLBCL) share similar histologic, clinical, and genetic features. In recent studies, we found that disease-specific chromosome 9p24.1/JAK2 amplification increased JAK2 expression and activity in both cHL and MLBCL. This prompted us to assess the activity of a clinical grade JAK2 selective inhibitor, fedratinib (SAR302503/TG101348), in in vitro and in vivo model systems of cHL and MLBCL with defined JAK2 copy numbers. EXPERIMENTAL DESIGN:We used functional and immunohistochemical analyses to investigate the preclinical activity of fedratinib and associated biomarkers in cell lines and murine xenograft models of cHL and MLBCL with known 9p24.1/JAK2 copy number. RESULTS:Chemical JAK2 inhibition decreased the cellular proliferation of cHL and MLBCL cell lines and induced their apoptosis. There was an inverse correlation between 9p24.1/JAK2 copy number and the EC50 of fedratinib. Chemical JAK2 inhibition decreased phosphorylation of JAK2, STAT1, STAT3, and STAT6 and reduced the expression of additional downstream targets, including PD-L1, in a copy number-dependent manner. In murine xenograft models of cHL and MLBCL with 9p24.1/JAK2 amplification, chemical JAK2 inhibition significantly decreased JAK2/STAT signaling and tumor growth and prolonged survival. In in vitro and in vivo studies, pSTAT3 was an excellent biomarker of baseline JAK2 activity and the efficacy of chemical JAK2 inhibition. CONCLUSIONS:In in vitro and in vivo analyses, cHL and MLBCL with 9p24.1/JAK2 copy gain are sensitive to chemical JAK2 inhibition suggesting that clinical evaluation of JAK2 blockade is warranted.
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Project description:Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of lymphoma that, like other Hodgkin lymphomas, has historically been treated aggressively. However, in most cases, NLPHL has an indolent course, which raises the question of to what extent these patients require aggressive upfront treatment. We describe the management and outcomes of consecutive NLPHL patients diagnosed at Memorial Sloan Kettering Cancer Center (MSK), with a focus on evaluating active surveillance. All patients aged 16 years or older diagnosed and followed at MSK between 1974 and 2016 were included. Treatment outcomes were compared between management with active surveillance and other strategies. We identified 163 consecutive patients who were treated with radiotherapy alone (46%), active surveillance (23%), chemotherapy (16%), combined modality (12%), or rituximab monotherapy (4%). Median follow-up was 69 months. Five-year progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) estimates were 85% (95% confidence interval [CI], 78-90), 97% (95% CI, 92-99), and 99% (95% CI, 95-100), respectively. Only 1 of 7 deaths was lymphoma related. Patients managed with active surveillance had slightly shorter PFS than those receiving any active treatment, with 5-year PFS of 77% (95% CI, 56-89) vs 87% (95% CI, 79-92; P = .017). This difference did not translate into better PFS2 or OS. Only 10 patients managed with active surveillance (27%) eventually required treatment, after a median of 61 months, and none died. NLPHL has an excellent prognosis. Within the limitations of a retrospective analysis, active surveillance is a viable initial management strategy for selected NLPHL patients.
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Project description:Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterized by a proliferation of fibroblasts in the tumor microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancer-associated fibroblasts. However, to date a deep molecular characterization of these fibroblasts is lacking. Thus, the aim of the present study is a comprehensive characterization of these fibroblasts. Gene expression profiling and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic phenotype characterized by myocardin (MYOCD) expression. Moreover, TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. As previously shown for other types of cancer-associated fibroblasts, treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin induced cell death. However, HRS cells adherent to fibroblasts were protected from Brentuximab-Vedotin induced injury. In summary, we confirm the importance of fibroblasts for HRS cell survival and identify TIMP3 which probably contributes as a major factor to the typical fibrosis observed in NS cHL.
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Project description:Hodgkin lymphoma (HL) represents a category of lymphoid neoplasms with unique features, notably the usual scarcity of tumour cells in involved tissues. The most common subtype of classical HL, nodular sclerosis HL, characteristically comprises abundant fibrous tissue stroma. Little information is available about the protein composition of the stromal environment from HL. Moreover, the identification of valid protein targets, specifically and abundantly expressed in HL, would be of utmost importance for targeted therapies and imaging, yet the biomarkers must necessarily be accessible from the bloodstream. To characterize HL stroma and to identify potentially accessible proteins, we used a chemical proteomic approach, consisting in the labelling of accessible proteins and their subsequent purification and identification by mass spectrometry. We performed an analysis of potentially accessible proteins in lymph node biopsies from HL and reactive lymphoid tissues, and in total, more than 1400 proteins were identified in 7 samples. We have identified several extracellular matrix proteins overexpressed in HL, such as versican, fibulin-1, periostin, and other proteins such as S100-A8. These proteins were validated by immunohistochemistry on a larger series of biopsy samples, and bear the potential to become targets for antibody-based anti-cancer therapies.
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