Metabolic signature and response to glutamine deprivation is independent of p53 status in B-cell malignancies

The tumour suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumours, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knock-out clones from distinct B-cell malignancies (ALL, CLL, DLBCL and MM). Metabolomics and isotope tracing showed that p53 loss did not drive a common metabolic signature. Instead, cell lines segregated according to cell of origin. Next, we focused on glutamine, as a crucial energy source in the B-cell tumour microenvironment. In both TP53 WT and KO cells, glutamine deprivation induced cell death through the integrated stress response (ISR), via CHOP/ATF4. Lastly, combining BH3 mimetic drugs with glutamine starvation emerged as a possibility to target resistant clones. In conclusion, our analyses do not support a common metabolic signature of p53 deficiency in B cell malignancies, and suggest therapeutic options for exploration based on glutamine dependency.