Mechanisms of NF-κB deregulation in lymphoid malignancies.
Deregulations promoting constitutive activation of canonical and non-canonical NF-κB signaling are a common feature of many lymphoid malignancies. Due to their cellular origin and the pivotal role of NF-κB for the normal function of B lymphocytes, B-cell malignancies are particularly prone to genetic aberrations that affect the pathway. Key positive regulators of NF-κB signaling can act as oncogenes that are often prone to chromosomal translocation, amplifications or activating mutations. Negative regulators of NF-κB have tumor suppressor functions and are frequently inactivated either by genomic deletions or point mutations. Whereas some aberrations are found in a variety of different lymphoid malignancies, some oncogenic alterations are very restricted to distinct lymphoma subsets, reflecting the clonal and cellular origin of specific lymphoma entities. NF-κB activation in many lymphoma cells is also driven by the microenvironment or chronic signaling that does not rely on genetic alterations. A number of drugs that target the NF-κB pathway are in preclinical or clinical development, revealing that there will be new options for therapies in the future. Since each lymphoma entity utilizes distinct mechanisms to activate NF-κB, a major challenge is to elucidate the exact pathological processes in order to faithfully predict clinical responses to the different therapeutic approaches.
Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany. Electronic address: daniel.krappmann@helmholtz-muenchen.de.
Daniel
D
Krappmann
Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
Michelle
M
Vincendeau
D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D051925:CD79 Antigens / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein / Q000378:metabolism; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
D053468:CARD Signaling Adaptor Proteins; D051925:CD79 Antigens; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase
B-cell receptor; Lymphoma; NF-κB