Upon activation of BCR, SRC family proteins (i.e., LYN) phosphorylate the ITAMs of CD79AB, which signals the recruitment of SYK in order to augment signaling.Institute of Oncology Research, Via Vela 6, 6500 Bellinzona, Switzerland.
MZL patients usually present an indolent clinical course, although the disease remains largely incurable, save early stage disease that might be irradiated. Therapeutic advances have been limited due to the small patient population, and have largely been adapted from other indolent lymphomas. Here, we discuss the numerous targets and pathways which may offer the prospect of directly inhibiting the mechanisms identified promoting and sustaining marginal zone lymphomagenesis. In particular, we focus on the agents that may have at least a theoretical application in the disease. Various dysregulated pathways converge to produce an overarching stimulation of nuclear factor B (NF-B) and the MYD88-IRAK4 axis, which can be thus leveraged or targeting B-cell receptor signaling through BTK inhibitors (such as ibrutinib, zanubrutinib, acalabrutinib) and PI3K inhibitors (such as idelalisib, copanlisib, duvelisib umbralisib) or via more novel agents in development such as MALT1 inhibitors, SMAC mimetics, NIK inhibitors, IRAK4 or MYD88 inhibitors. NOTCH signaling is also crucial for marginal zone cells, but no clinical data are available with NOTCH inhibitors such as the -secretase inhibitor PF-03084014 or the NICD inhibitor CB-103. Simatic manager v56 free downloadThe hypermethylation phenotype, the overexpression of the PRC2-complex or the presence of TET2 mutations reported in MZL subsets make epigenetic agents (demethylating agents, EZH2 inhibitors, HDAC inhibitors) also potential therapeutic tools for MZL patients. Eminem slim shady lp 320 zip sharebeastThe disease is generally divided into three distinct categories based on clinical and molecular characteristics: extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT); nodal marginal zone lymphoma (NMZL); and lastly, splenic marginal zone lymphoma (SMZL) ( 1, 2 ). The MZLs as a whole represents the second most common type of indolent B-cell lymphoma, comprising approximately 6 of all non-Hodgkin lymphomas (NHL) cases ( 3 ). Despite their varying clinical presentations, the three entities share common features including an association with antigen stimulation, presence of specific translocations, and importantly, the activation of the nuclear factor B (NF-B) pathway. In an effort to appreciate these opportunities, we have structured concepts around specific therapeutic interventions in the context of the underlying deranged biology. Genomic profiling has had a substantial impact on our understanding of the molecular pathogenesis of MZL ( 4 - 19 ). These experiences have identified critical aberrations in the function of the B-cell receptor (BCR), NF-B, Janus kinase (JAK)signal transducers and activators of transcription (STAT), and Toll-Like ReceptorInterleukin (TLRIL) signaling, each of which has at least one therapeutic agent that could impact that biology. Herein, we underscore that biology and the agents that may have at least a theoretical application in the disease. The NF-B family of transcription factors is comprised of five structurally related genes: NFKB1 (p105 and p50), NFKB2 (p100 and p52), RELA (p65), RELB (RelB), and REL (c-Rel) ( 20 ). Activation of the NF-B family of transcription factors can occur through two distinct pathways: canonical (classical) and non-canonical (alternative). Alternatively, the non-canonical pathway is induced by B-cell activating factor belonging to the TNF family (BAFF) receptor, and CD40 ( 21 ), both of which leads to the activation of NF-B inducible kinase (NIK) and IB kinase (IKK), leading to phosphorylation and proteolysis of p100 that in turn creates the active subunit, p52. The p52-RelB heterodimer translocates into the nucleus in order to induce transcriptional activation of genes involved in cycle cell progression and proliferation ( 20, 21 ). Fifteen to thirty percent of all MZL harbor inactivating mutationsdeletions in TNFAIP3 (A20), which codes for a key negative regulator of NF-B pathway, thus representing one of the most common genetic events contributing to overactivation of the NF-B pathway in MZL ( 7, 9, 27 ). These agents may include those targeting BCR signaling through Brutons Tyrosine Kinase (BTK) inhibitors and phosphatidylinositol 3-kinase (PI3K) inhibitors to more novel agents in development such as MALT1 inhibitors. BCR signaling dysregulation is a hallmark of MZL and can mimic antigen dependent BCR activation.
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