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

Chiara Montironi; Zhenghao Chen; Ingrid A M Derks; Gaspard Cretenet; Esmée A Krap; Eric Eldering; Helga Simon-Molas

doi:10.1016/j.isci.2024.109640

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

iScience. 2024 Mar 28;27(5):109640. doi: 10.1016/j.isci.2024.109640. eCollection 2024 May 17.

Authors

Chiara Montironi^{1

2

3}, Zhenghao Chen^{1

2

3}, Ingrid A M Derks^{1

2

3}, Gaspard Cretenet^{1

2

3}, Esmée A Krap¹, Eric Eldering^{1

2

3}, Helga Simon-Molas^{1

2

3

4}

Affiliations

¹ Amsterdam UMC Location University of Amsterdam, Department of Experimental Immunology, Amsterdam, the Netherlands.
² Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, the Netherlands.
³ Cancer Center Amsterdam, Cancer Immunology, Amsterdam, the Netherlands.
⁴ Amsterdam UMC Location University of Amsterdam, Department of Hematology, Amsterdam, the Netherlands.

Abstract

The tumor suppressor p53 has been described to control various aspects of metabolic reprogramming in solid tumors, but in B cell malignancies that role is as yet unknown. We generated pairs of p53 functional and knockout (KO) clones from distinct B cell malignancies (acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma). 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 tumor microenvironment. In both TP53 wild-type and KO cells, glutamine deprivation induced cell death through the integrated stress response, 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.

Keywords: Cancer; Cell biology; Metabolomics; Microenvironment.