title: NF-κB activation in chronic lymphocytic leukemia: A point of convergence of external triggers and intrinsic lesions.
abstract: The nuclear factor-κB (NF-κB) pathway is constitutively activated in chronic lymphocytic leukemia (CLL) patients, and hence plays a major role in disease development and evolution. In contrast to many other mature B-cell lymphomas, only a few recurrently mutated genes involved in canonical or non-canonical NF-κB activation have been identified in CLL (i.e. BIRC3, MYD88 and NFKBIE mutations) and often at a low frequency. On the other hand, CLL B cells seem 'addicted' to the tumor microenvironment for their survival and proliferation, which is primarily mediated by interaction through a number of cell surface receptors, e.g. the B-cell receptor (BcR), Toll-like receptors and CD40, that in turn activate downstream NF-κB. The importance of cell-extrinsic triggering for CLL pathophysiology was recently also highlighted by the clinical efficacy of novel drugs targeting microenvironmental interactions through the inhibition of BcR signaling. In other words, CLL can be considered a prototype disease for studying the intricate interplay between external triggers and intrinsic aberrations and their combined impact on disease evolution. In this review, we will discuss the current understanding of mechanisms underlying NF-κB deregulation in CLL, including micro-environmental, genetic and epigenetic events, and summarize data generated in murine models resembling human CLL. Finally, we will also discuss different strategies undertaken to intervene with the NF-κB pathway and its upstream mediators.
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Larry
authors: L
authors: Mansouri
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors: Nikos
authors: N
authors: Papakonstantinou
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors: Stavroula
authors: S
authors: Ntoufa
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Institute of Applied Biosciences, CERTH, Thessaloniki, Greece.
authors: Kostas
authors: K
authors: Stamatopoulos
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: richard.rosenquist@igp.uu.se.
authors: Richard
authors: R
authors: Rosenquist
mesh_terms: D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051193:Toll-Like Receptors; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein
keywords: Chronic lymphocytic leukemia; Gene mutations; Microenvironment; NF-κB