Hodgkin Lymphoma : NF-κB Pathway
Image Description
NF-κB Pathway in Classic Hodgkin Lymphoma (cHL) : Several genes are mutated or dysregulated in cHL, altering key pathways involved in cell proliferation, cell survival, and immune escape. One of the main molecular events in the pathogenesis of cHL is constitutive activation of NF-κB pathway in Hodgkin and Reed-Sternberg (HRS) cells. This is accomplished in one of many ways.
Cytokines, chemokines, and ligands associated with interleukins in the tumor microenvironment can directly activate the NF- κB pathway. This initiates a complex intracellular signaling cascade which results in transcription of several genes involved in proliferation, cell survival, and evasion of apoptosis.
Latent Membrane Protein-1 (LMP-1): In EBV+ cases of cHL (75% of mixed cellularity and lymphocyte depleted, 10-25% of nodular sclerosis, 40% of lymphocyte-rich cases), LMP-1 encoded by the EBV genome mimics an activated TNF receptor and upregulates NF-κB pathway.
Mutations in Negative Regulators: The activation of NF-κB can also occur via acquired loss-of-function mutations in negative regulators of this pathway. Examples include mutations in NFKBIA and NFKBIE genes (10%-20% of cases) which encode IκB; and TNFAIP3 gene (40% of cases) encoding TNF-α-induced protein 3 (A20). Most TNFAIP3-mutated cHL cases are negative for EBV and these two transforming events appear to be mutually exclusive.
Gains in Positive Regulators: Genomic gains and amplification of REL proto-oncogene on chromosome 2p16 (40% of cHL) and NIK (25% of cases) also play a role in NF-κB upregulation.
Rare Mutations: Other regulators of NF-κB pathway, including BCL3 and tumor suppressor genes CYLD and TRAF3 are mutated in HRS cells in rare cases of cHL.
Image credit: Boghog2 at English Wikipedia, Public domain, via Wikimedia Commons
Cytokines, chemokines, and ligands associated with interleukins in the tumor microenvironment can directly activate the NF- κB pathway. This initiates a complex intracellular signaling cascade which results in transcription of several genes involved in proliferation, cell survival, and evasion of apoptosis.
Latent Membrane Protein-1 (LMP-1): In EBV+ cases of cHL (75% of mixed cellularity and lymphocyte depleted, 10-25% of nodular sclerosis, 40% of lymphocyte-rich cases), LMP-1 encoded by the EBV genome mimics an activated TNF receptor and upregulates NF-κB pathway.
Mutations in Negative Regulators: The activation of NF-κB can also occur via acquired loss-of-function mutations in negative regulators of this pathway. Examples include mutations in NFKBIA and NFKBIE genes (10%-20% of cases) which encode IκB; and TNFAIP3 gene (40% of cases) encoding TNF-α-induced protein 3 (A20). Most TNFAIP3-mutated cHL cases are negative for EBV and these two transforming events appear to be mutually exclusive.
Gains in Positive Regulators: Genomic gains and amplification of REL proto-oncogene on chromosome 2p16 (40% of cHL) and NIK (25% of cases) also play a role in NF-κB upregulation.
Rare Mutations: Other regulators of NF-κB pathway, including BCL3 and tumor suppressor genes CYLD and TRAF3 are mutated in HRS cells in rare cases of cHL.
Image credit: Boghog2 at English Wikipedia, Public domain, via Wikimedia Commons
