Hodgkin Lymphoma : JAK-STAT Pathway
JAK-STAT Pathway in Classic Hodgkin Lymphoma (cHL): Besides NF-κB pathway, there is also constitutive activation of JAK/STAT pathway in cHL. This can result from 9p24 amplification (which contains JAK2, PD1L1, and PD1L2 genes) as well as following inactivating mutations in the negative regulators of JAK/STAT pathway such as SOCS1 (60% of cases) and PTPN1. One study reported hotspot mutations in STAT6 in 30% of cases. JAK-STAT pathway activation causes hyperphosphorylation of multiple STAT proteins which transcriptionally upregulate several target genes. In addition, Notch-1, PI3K/AKT, and MAPK/ERK pathways also appear to be dysregulated in Hodgkin and Reed-Sternberg (HRS) cells. The HRS cells interact with the immune effector cells in their microenvironment. They also influence their surroundings by secreting a variety of cytokines, including TNF-α, TGF-β, interferon-γ, interleukins (IL-2, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, and IL-13); and chemokines, including eotaxin (which attracts eosinophils), TARC, and MIP1α. These cytokines/chemokines underlie the pathogenesis of reactive inflammatory infiltrate, help RS cells grow and survive, and cause systemic symptoms.