Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of B-cell lymphoma lines with an immature phenotype has been used as a model system to study molecular events associated with receptor ligation induced death. B-cell receptor (BCR) cross-linking with antibodies to membrane IgM (but not with anti IgD) induces c-Myc downregulation via nuclear factor kappaB inactivation and p27(Kip1) accumulation in these B lymphomas. Anti-mu-treated cells then undergo G1 arrest and die by apoptosis independent of Fas. Steroids and retinoids similarly downregulate c-Myc and induce apoptosis in these B cells and synergize with anti-mu. Rescue from apoptosis induced by anti-mu or steroids occurs with T-cell signals, like CD40L, or a broad-range caspase inhibitor, but only CD40L prevents the loss of c-Myc, p27 accumulation and growth arrest. Both IgM and IgD signaling lead to modulation of phosphatidylinositol 3-kinase (PI3K) signals, including the activation of p70(S6K), but this pathway recovers under anti-IgD treatment. Blockade of the PI3K pathway augments anti-mu-induced death and converts anti-delta to an apoptotic signal. Resistance to Fas-mediated death may be an important factor in B-cell transformation in vivo. Many of our panel of lymphomas are insensitive to Fas-mediated death signals, although all can form a death-inducing signaling complex (DISC). Additional studies suggest that some lymphomas can be blocked at the DISC complex by anti-apoptotic proteins, whereas others are inhibited downstream of caspase 8 activation. Anti-Ig treatment of a Fas-sensitive line, A20.2J, activated a number of genes whose products may block apoptosis proximally (like FLICE-inhibitory protein (FLIP1)) or at late points, such as bcl-2-family members. Our data suggest that B lymphomas develop multiple pathways of resistance to Fas-mediated signals during lymphomagenesis, in part via signaling through the BCR.
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PMID:B-cell receptor and Fas-mediated signals for life and death. 1104 71

The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter's Syndrome (RS) and it is a rare event with dismal prognosis. In this study, we conducted whole genome sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 clinical trial (CHOP-O) patients. We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumour necrosis factor receptor associated factor three (TRAF3). In the non-coding genome, we discovered AID-related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2 andTRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal de-convolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study (NCT03899337).
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PMID:Genomic and transcriptomic correlates of Richter's transformation in Chronic Lymphocytic Leukemia. 3320 36