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Hodgkin’s lymphoma (HL) accounts for around 11% of all malignant lymphomas. The morphologic hallmarks of this unique lymphoma were initially described more than 100 years ago; it is characterized by the presence of Hodgkin Reed-Sternberg (HRS) cells in classical HL (cHL) and so-called lymphocyte-predominant (LP) cells in nodular lymphocyte-predominant HL (NLPHL). Typically, malignant cells are greatly outnumbered by reactive cells in a microenvironment that includes eosinophils, lymphocytes, macrophages, plasma cells, mast cells, stromal cells, fibroblasts, and other cells. Specifically, in cHL, the frequencies of all these cellular components, including the HRS cells, vary considerably between cHL subtypes; lymphocyte depleted, lymphocyte rich, mixed cellularity (MC), and nodular sclerosis (NS).
HRS cells show a deregulated activity of multiple signaling pathways and transcription factors that have essential roles in the pathophysiology of these cells. The canonical and the noncanonical NFκB pathway are constitutively activated in HRS cells, and NFκB function is important for the survival of HRS cells. The activation of NFκB is presumably mediated in part by signaling through several cell-surface receptors, including CD40 and RANK. However, genetic lesions in HRS also play an important role. In addition, in approximately 40% of classical HL the HRS cells are latently infected by EBV and, in these cases, the EBV-encoded latent membrane protein 1 (LMP1) is expressed, which activates NFκB by mimicking an activated CD40 receptor.
A number of cytokines signal through the JAK/STAT pathway, in which upon cytokine binding, cytokine receptors activate the JAK kinases, which then phosphorylate the STAT proteins, causing translocation of STAT homo- or heterodimers into the nucleus, where they function as transcription factors. HRS cells harbor active STAT3, STAT5, and STAT6 factors, and several cytokines contribute to the activation of this pathway, including IL-13 and IL-21. These cytokines may be produced by other cells in the microenvironment, but some are also secreted by HRS cells, causing autocrine stimulation. Other signaling pathways that are typically only transiently activated in B cells upon specific activation but which are constitutively active in HRS cells include the MEK/ERK pathway and the PI3K/Akt pathway. HRS cells also show activation of numerous pathways and transcription factors that are not physiologically seen in normal B cells, including multiple receptor tyrosine kinases, the T-cell transcription factors Notch-1 and GATA-3, the myeloid receptor CSF1R, and the natural killer cell factor ID2.
Due to the increased expression of members of the TNF receptor family and the dependence of malignant cells on TNF receptor downstream signaling, these molecules are considered ideal targets for specific agents in HL. TNFRSF8 (CD30) in particular has been the target of a number of preclinical and clinical studies, of which the anti-CD30 compounds SGN-30 and MDX060 can be considered representative but disappointing in phase I/II clinical trials because of limited efficacy in relapsed disease. Many novel drugs have downstream receptor signaling as their primary targets, of which everolimus (mammalian target of rapamycin, phosphoinositide 3-kinase pathway), bortezomib (TNFR signaling, NFκB pathway), and vorinostat (STAT6, IL signaling) have shown promising preclinical results. Of these, however, bortezomib as a single agent in relapsed HL had low clinical efficacy. Combination therapies are now being tested.
Creative Biogene, as a leading biotechnology company, is able to offer various Hodgkin’s lymphoma pathway related products including stable cell lines, viral particles and clones for your pathogenesis study and drug discovery projects.