Metabolic Convergence on Lipogenesis in RAS, BCR-ABL, and MYC-driven Lymphoid Malignancies

Abstract

Background Metabolic re-programming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, although 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, in lymphoid malignancies tumor cells often share similar environments and potentially similar metabolic profiles. Methods We searched publicly available data sets for common metabolic convergence in lymphoma and leukemia. Using in vitro cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models we examine metabolic profiles of lipogenesis. We then 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 unpaired T tests and one-way ANOVA. Results We find that de novo lipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived in 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). We identify specific cell death responses to TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in transplanted lymphoma cell lines. We also observed 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 feature of MYC high expressing lymphoma cell lines. Conclusions These studies indicate that inhibition of lipogenesis may be a common survival strategy for many lymphomas and that high MYC expression is predictive of sensitivity to blockade of fatty acid synthesis. Trial Registration This study does not include any clinical interventions on human subjectsTrial RegistrationThis study does not include any clinical interventions on human subjects