Identification of a new gene regulatory circuit involving B cell receptor activated signaling using a combined analysis of experimental, clinical and global gene expression data

Abstract

To discover new regulatory pathways in B lymphoma cells, we performed a combined analysis of experimental, clinical and global gene expression data. We identified a specific cluster of genes that was coherently expressed in primary lymphoma samples and suppressed by activation of the B cell receptor (BCR) through αIgM treatment of lymphoma cells in vitro. This gene cluster, which we called BCR.1, includes numerous cell cycle regulators. A reduced expression of BCR.1 genes after BCR activation was observed in different cell lines and also in CD10+ germinal center B cells. We found that BCR activation led to a delayed entry to and progression of mitosis and defects in metaphase. Cytogenetic changes were detected upon long-term αIgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc co-regulated genes in distinct groups of lymphoma patients was observed. Finally, we showed that the BCR.1 index discriminates activated B cell-like and germinal centre B cell-like diffuse large B cell lymphoma supporting the functional relevance of this new regulatory circuit and the power of guided clustering for biomarker discovery.

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

“…Such links to human disease have been particularly reinforced by many non-focal publications ( Table S3; Data Table S2 ). Indeed, expression of DUF34 in eukaryotes has been associated with several human pathologies, including cancers [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 ], chemotherapeutic drug response [ 94 , 95 ], psychiatric disorders [ 96 , 97 ], cardiovascular disease [ 98 , 99 , 100 ], insulin resistance [ 101 ], osteoporosis [ 75 , 102 ], inflammation [ 103 ], Amyotrophic Lateral Sclerosis (ALS) [ 30 , 104 ], William-Beuren Syndrome [ 31 ], as well as several other degenerative and developmental neurological diseases [ 76 , 105 , 106 ]. The regulation of DUF34 homologs by retinoic acid or biochemical relatives (e.g., all-trans retinoic acid, ATRA; testosterone [Comparative Toxicogenomics Database]) appears to be conserved between humans, mice, and select life stages of some insects [ 73 , 107 , 108 , 109 ].…”

Genome‐wide DNA methylation analysis along the progression of gastric marginal zone B‐cell lymphoma of mucosa‐associated lymphoid tissue (MALT) type

“…One of the genes with a negative correlation between DNA methylation and RNA expression was cell division cycle associated 8 ( CDCA8 ) showing a decrease in the promoter methylation and an increase in mRNA (Pearson correlation, ρ = −0·86, P = 0·0011) and protein expression for LC‐ in comparison to SC‐MZBL (Fig 2, Table SVII). CDCA8 is required for microtubule stabilisation and spindle formation during mitosis and is influenced via the B‐cell receptor in some diffuse large B‐cell lymphomas 14 . Taken together, we saw a decreased expression for 3·10% of hypermethylated genes in LC‐ in comparison to SC‐MZBL, while 96·56% showed no difference in expression.…”

“…CDCA8 is required for microtubule stabilisation and spindle formation during mitosis and is influenced via the B-cell receptor in some diffuse large B-cell lymphomas. 14 Taken together, we saw a decreased expression for 3Á10% of hypermethylated genes in LC-in comparison to SC-MZBL, while 96Á56% showed no difference in expression.…”

Comparative Genomic Analysis of the DUF34 Protein Family Suggests Role as a Metal Ion Chaperone or Insertase

“…Data Table 2). Indeed, expression of DUF34 in eukaryotes has been associated with several human pathologies, including cancers [78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94], chemotherapeutic drug response [95,96], psychiatric disorders [97,98], cardiovascular disease [99][100][101], insulin resistance [102], osteoporosis [76,103], inflammation [104], Amyotrophic Lateral Sclerosis (ALS) [30,105], William-Beuren Syndrome [31], as well as several other degenerative and developmental neurological diseases [77,106,107]. The regulation of DUF34 homologs by retinoic acid or biochemical relatives (e.g., all-trans retinoic acid, ATRA; testosterone [Comparative Toxicogenomics Database]) appears to be conserved between humans, mice and select life stages of some insects [74,[108][109][110].…”