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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 [tonsil]

ABSTRACT: To discover new essential regulatory pathways in B lymphoma cells a combined analysis of experimental and clinical high throughput data was performed. Among others, a specific cluster of coherently expressed genes named BCR.1 was identified in primary lymphoma samples. These coherently expressed genes are suppressed by α-IgM treatement of lymphoma cells in vitro. This B cell receptor activation leads to a G2 phase prolongation, delayed entry into the M phase, an overall diminished capacity of the cells to enter into mitosis and defects in metaphases. Cytogenetic changes are detected under long term α-IgM treatment. Furthermore, an inverse correlation of BCR.1 genes with c-Myc coregulated genes in distinct groups of lymphoma patients is observed. In addition to the impact of c-Myc in the regulation of cell cycle regulators, BCR.1 genes are regulated by a combined action of IKK2, MAPK14 and JNK. Finally, the BCR.1 index discriminates activated B cell like and germinal centre B cell like diffuse large B cell lymphoma. Therefore, a new regulatory circuit is described affecting cell cycle and chromosome instability in B cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE71724 | GEO | 2016/06/07

SECONDARY ACCESSION(S): PRJNA291922

REPOSITORIES: GEO

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Project description:Similar to resting mature B cells, where the B-cell antigen receptor (BCR) is essential for cellular survival, surface BCR expression is conserved in most mature B cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signaling is required for tumour cell survival. Consequently, the BCR signaling machinery has become a new target in the therapy of B cell malignancies. Here, we studied the effects of BCR ablation on MYC-driven mouse B cell lymphomas and compared them to observations in human Burkitt lymphoma. Whereas BCR ablation did not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappeared in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This required neither cellular contact, nor factors released by BCR+ tumour cells. Instead, BCR loss induced the rewiring of central carbon metabolism increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuated GSK3β activity to support MYC-controlled gene expression. BCR- tumour cells exhibited increased GSK3β activity and were rescued from their competitive growth disadvantage by GSK3β. BCR-negative lymphoma variants that restored competitive fitness, normalized GSK3β following constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate Ig-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR-less tumour cells. In this dataset, we included the expression data obtained from BCR-positive (BCR+), BCR-negative (BCR-) and BCR-independent lymphoma cells co-cultured for four days in presence or absence of GSK3b inhibitor, CHIR99021. This data was used to a) identify genes regulated by the BCR through GSK3b inhibition, and b) identify genes that confers BCR-independency to lymphoma variants resistant to BCR loss.

Project description:Similar to resting mature B cells, where the B-cell antigen receptor (BCR) is essential for cellular survival, surface BCR expression is conserved in most mature B cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signaling is required for tumour cell survival. Consequently, the BCR signaling machinery has become a new target in the therapy of B cell malignancies. Here, we studied the effects of BCR ablation on MYC-driven mouse B cell lymphomas and compared them to observations in human Burkitt lymphoma. Whereas BCR ablation did not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappeared in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This required neither cellular contact, nor factors released by BCR+ tumour cells. Instead, BCR loss induced the rewiring of central carbon metabolism increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuated GSK3β activity to support MYC-controlled gene expression. BCR- tumour cells exhibited increased GSK3β activity and were rescued from their competitive growth disadvantage by GSK3β. BCR-negative lymphoma variants that restored competitive fitness, normalized GSK3β following constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate Ig-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR-less tumour cells. In this dataset, we included the expression data obtained from BCR-positive (BCR+) and BCR-negative (BCR-) lymphoma cells co-cultured for 4 days in presence or absence of GSK3b inhibitor, CHIR99021. These data were used to obtain genes that are regulated by the BCR through GSK3b inhibition.

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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 [tonsil]

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