Abstract
BCR-proficient lymphoma cells exhibit a competitive growth advantage in vitro and in vivo.
Major finding: BCR-proficient lymphoma cells exhibit a competitive growth advantage in vitro and in vivo.
Concept: BCR− lymphoma cells have increased GSK3β activity and GSK3β inhibition rescues their growth disadvantage.
Impact: BCR-targeted therapies may be enhanced by the addition of inhibitors that target BCR− tumor cells.
Most mature B-cell lymphomas express cell surface B-cell antigen receptor (BCR), and BCR knockdown confers a growth impairment. To better understand the role of BCR ablation in B-cell lymphoma, Varano, Raffel, and colleagues used a mouse model of MYC-driven mouse B-cell lymphoma. Lymphoma cells continued to grow following BCR ablation both in vitro and in vivo, but, when BCR+ and BCR− tumor cells were cocultured, the BCR+ cells outcompeted the BCR− cells in vitro and in vivo. BCR− cells exhibited delayed G1/S cell-cycle transition and increased apoptosis. Moreover, in serum-limiting conditions the BCR− tumor cells were outcompeted more quickly. Mechanistically, BCR− cells exhibited increased breakdown of exogenous carbon sources to sustain the tricarboxylic acid cycle, allowing BCR+ cells to outcompete BCR− cells in nutrient-limiting conditions. BCR loss impaired GSK3β phosphorylation, thereby relieving GSK3β inhibition and increasing its activity. Consequently, a GSK3β inhibitor promoted cell-cycle progression in BCR− cells and abolished the growth advantage of BCR+ cells. Further, GSK3β inhibition supported the expression of BCR-controlled genes in MYC-transformed B cells, including genes involved in cell-cycle progression, DNA replication, DNA damage response, and energy metabolism. Additionally, most BCR–GSK3β controlled genes were bound by MYC, suggesting that BCR regulates MYC controlled gene expression to promote lymphoma cell fitness. A subset of BCR− lymphoma cells persisted in competition assays with BCR+ cells, and the BCR-independent lymphoma cells exhibited an improved G1-to-S transition, a PI3Kδ-independent normalization of GSK3β phosphorylation, and increased expression of MYC target genes. Further, activation of MAPK signaling by Ras activating mutations could render BCR− cells BCR-independent. These findings may be clinically relevant, as 5 of 30 (17%) patients with Burkitt lymphoma had lost BCR expression in at least a fraction of the cells. Collectively, these findings demonstrate that BCR loss alters carbon metabolism and increases GSK3β activity to reduce competitive fitness, but suggest that BCR-targeted therapies may be beneficial in combination with therapies targeting BCR− tumor cells.
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