Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies
Authors: Liefwalker Daniel F. , Ryan Meital , Wang Zhichao , Pathak Khyatiben V. , Plaisier Seema , Shah Vidhi , Babra Bobby , Dewson Gabrielle S. , Lai Ian K. , Mosley Adriane R. , Fueger Patrick T. , Casey Stephanie C. , Jiang Lei , Pirrotte Patrick , Swaminathan Srividya , Sears Rosalie C. 
Published: August 2021

Background

Metabolic reprogramming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, often having unintended side effects on normal metabolic programs and limited efficacy due to integrative nature of metabolic substrate sourcing. Although the initiating oncogenic lesion may vary, tumor cells in lymphoid malignancies often share similar environments and potentially similar metabolic profiles. We examined cells from mouse models of MYC-, RAS-, and BCR-ABL-driven lymphoid malignancies and find a convergence onde novolipogenesis. We explore the potential role of MYC in mediating lipogenesis by13C glucose tracing and untargeted metabolic profiling. Inhibition of lipogenesis leads to cell death bothin vitroandin vivoand does not induce cell death of normal splenocytes.

Methods

We analyzed RNA-seq data sets for common metabolic convergence in lymphoma and leukemia. Usingin vitrocell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models and oncogene-driven human cell lines, we determined gene regulation, metabolic profiles, and sensitivity to inhibition of lipogenesis in lymphoid malignancies. We utilize preclinical murine models and transgenic primary model of T-ALL to determine the effect of lipogenesis blockade across BCR-ABL-, RAS-, and c-MYC-driven lymphoid malignancies. Statistical significance was calculated using unpairedt-tests and one-way ANOVA.

Results

This study illustrates thatde novolipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived from conditional MYC, RAS, and BCR-ABL transgenic murine models, we demonstrate shared responses to inhibition of lipogenesis by the acetyl-coA carboxylase inhibitor 5-(tetradecloxy)-2-furic acid (TOFA), and other lipogenesis inhibitors. We performed metabolic tracing studies to confirm the influence of c-MYC and TOFA on lipogenesis. We identify specific cell death responses to TOFAin vitroandin vivoand demonstrate delayed engraftment and progressionin vivoin transplanted lymphoma cell lines. We also observe delayed progression of T-ALL in a primary transgenic mouse model upon TOFA administration. In a panel of human cell lines, we demonstrate sensitivity to TOFA treatment as a metabolic liability due to the general convergence onde novolipogenesis in lymphoid malignancies driven by MYC, RAS, or BCR-ABL. Importantly, cell death was not significantly observed in non-malignant cellsin vivo.

Conclusions

These studies suggest thatde novolipogenesis may be a common survival strategy for many lymphoid malignancies and may be a clinically exploitable metabolic liability.

Trial registration

This study does not include any clinical interventions on human subjects.