Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma

Abstract

IntroductionHodgkin lymphoma (HL), one of the most frequent lymphomas, is composed of 2 entities: classical HL (cHL), accounting for ϳ 95% of cases, and the rare nodular lymphocyte predominant HL (nLPHL). 1 Tumor cells are named LP cells in nLPHL and Hodgkin and Reed-Sternberg (HRS) cells in cHL. Based on differences in the histologic picture and composition of the microenvironment, cHL is subtyped into nodular sclerosis (NS), mixed cellularity (MC), lymphocyte-rich (LR), and lymphocytedepleted (LD) cHL. 1 HL is very unusual as the tumor cells often account for Ͻ 1% of the cellular population in affected lymph nodes. In cHL, the majority of cells consists of T and B cells, macrophages, and other cell types. The rarity of HRS cells and the existence of only few cHL-derived cell lines have hampered their molecular analysis. Nevertheless, studies of microdissected HRS cells demonstrated that they derive from germinal center (GC) or post-GC B cells because they carry somatically mutated immunoglobulin (Ig) V genes. 2 Destructive IgV gene mutations in a fraction of cases suggest a derivation of HRS cells from GC B cells that acquired such mutations and normally would undergo apoptosis. 3,4 In ϳ 40% of cHL, HRS cells are latently infected by Epstein-Barr virus (EBV), and EBV is likely capable to rescue preapoptotic GC B cells from apoptosis. 5 There is intensive discussion about the relationship between cHL and B-cell non-HL (B-NHL). In particular, cHL shares with primary mediastinal B-cell lymphoma (PMBL) several genetic, immunophenotypic, and biologic characteristics, and the NS-cHL subtype often has also a similar clinical presentation. [6][7][8] Furthermore, gene expression profiling studies showed that part of the signature distinguishing PMBL from diffuse large B-cell lymphomas (DLBCLs) is detected also in cHL cell lines. 9,10 However, the histopathologic picture of these neoplasms is typically quite different. Moreover, additional biologic/diagnostic "gray zones" at the interface between cHL and other B-cell lymphomas, such as nLPHL, T cell/histiocyterich B-cell lymphoma (TCRBL) and DLBCL have been described. 1,8,11,12 We previously performed genome-wide expression studies on cHL cell lines compared with B-NHL and normal B cells, thereby identifying genes aberrantly expressed by HRS cells and uncovering a dramatic loss of the B-cell transcriptional program in cHL. 13,14 However, isolated HRS cells cultured in suspension might not faithfully portray the gene expression program of primary HRS cells in the lymph node microenvironment. Whole-tissue RNA analysis was valuable in characterizing the cHL microenvironment but not the HRS cells. [15][16][17] We recently established an approach to perform genome-wide expression profiling of cells laser-microdissected from frozen biopsies and initially characterized the tumor cells of nLPHL and anaplastic large cell lymphoma. 18 Methods Normal and neoplastic B-cell samplesThe isolation of naive (N) and memory (M) B cells from peripheral blood of 5 healthy adult donors, and...

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

“…Apart from a few studies investigating the proliferation potential of RS cells (13,14,28), the giant cell population has not been characterized in detail up to now. Most previous functional studies used the bulk of HL cell lines, ignoring cellular heterogeneity (18,(29)(30)(31). Tracking of individual HRS cells and their progeny over time has allowed us to dissect giant cell dynamics within the heterogeneous cultures of three HL cell lines and to link HRS cell behavior, RS cell development, and the future fate of these cells.…”

The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells

“…Remarkably, we 5 also found a prominent enrichment of clusters related to inflammatory processes, such as cytokine production and activity, receptor-ligand or cell-cell interactions and lymphocyte activation (Supplementary Table 3 Table 5), but are also prominent components of deregulated functional pathways in HRS cells. 14,15 As a major feature of the cellular response to IL-15 stimulation, we identified a significant induction of cytokines and chemokines in HRS cells. Several of these factors, such as IL-6, IL-9 and CCL3, in turn may have the potential to mediate growth and survival signals for HRS cells as well as to attract or stimulate cells of the tumor microenvironment.…”

“…Remarkably, we 5 also found a prominent enrichment of clusters related to inflammatory processes, such as cytokine production and activity, receptor-ligand or cell-cell interactions and lymphocyte activation (Supplementary Table 3 Table 5), but are also prominent components of deregulated functional pathways in HRS cells. 14,15 As a major feature of the cellular response to IL-15 stimulation, we identified a significant …”

Identification of Novel Inherited Genetic Markers for Aggressive PCa in European and African Americans Using Whole Genome Sequencing

“…It encodes a Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol (3,4,5)-triphosphate (PtdIns (3,4,5) P3) to produce PtdIns(3,4)P2, and therefore negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Acting as an inhibitor of the PI3K pathway, INPP5D is considered as a tumor suppressor in acute myeloid leukemia, Hodgkin's lymphoma, and acute lymphoblastic leukemia (Luo et al 2004;Metzner et al 2009;Tiacci et al 2012). Besides, INPP5D has been identified as the target of the cellular tumor antigen p53 in human breast cancer adenocarcinoma MCF7 cells and testicular germ cell tumor-derived human embryonal carcinoma cells (Kerley-Hamilton et al 2005;Lion et al 2013).…”