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 on de novo lipogenesis. We explore the potential role of MYC in mediating lipogenesis by 13C glucose tracing and untargeted metabolic profiling. Inhibition of lipogenesis leads to cell death both in vitro and in vivo and does not induce cell death of normal splenocytes. We analyzed RNA-seq 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 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 unpaired t-tests and one-way ANOVA. This study illustrates that de novo lipid 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 TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in 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 on de novo lipogenesis in lymphoid malignancies driven by MYC, RAS, or BCR-ABL. Importantly, cell death was not significantly observed in non-malignant cells in vivo. These studies suggest that de novo lipogenesis may be a common survival strategy for many lymphoid malignancies and may be a clinically exploitable metabolic liability. This study does not include any clinical interventions on human subjects.

中文翻译：

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RAS、BCR-ABL 和 MYC 驱动的淋巴恶性肿瘤中脂肪生成的代谢趋同


代谢重编程是许多癌症亚型的核心特征，也是癌症的标志。许多治疗策略试图利用这一特征，但由于代谢底物来源的综合性质，通常会对正常代谢程序产生意想不到的副作用，并且疗效有限。尽管起始致癌病变可能有所不同，但淋巴恶性肿瘤中的肿瘤细胞通常具有相似的环境和潜在相似的代谢特征。我们检查了 MYC、RAS 和 BCR-ABL 驱动的淋巴恶性肿瘤小鼠模型的细胞，发现脂肪从头生成的趋同性。我们通过 13C 葡萄糖追踪和非靶向代谢分析探索 MYC 在介导脂肪生成中的潜在作用。脂肪生成的抑制会导致体外和体内细胞死亡，但不会诱导正常脾细胞的细胞死亡。我们分析了淋巴瘤和白血病常见代谢趋同的 RNA-seq 数据集。使用源自条件 MYC、RAS 和 BCR-ABL 转基因小鼠模型和癌基因驱动的人类细胞系的体外细胞系，我们确定了淋巴恶性肿瘤中的基因调控、代谢特征和对脂肪生成抑制的敏感性。我们利用临床前小鼠模型和 T-ALL 转基因初级模型来确定脂肪生成阻断对 BCR-ABL、RAS 和 c-MYC 驱动的淋巴恶性肿瘤的影响。使用未配对 t 检验和单向方差分析计算统计显着性。这项研究表明，从头脂质生物发生是几种淋巴瘤亚型的共同特征。 使用源自条件 MYC、RAS 和 BCR-ABL 转基因小鼠模型的细胞系，我们证明了对乙酰辅酶 A 羧化酶抑制剂 5-(十四氧基)-2-糠酸 (TOFA) 和其他脂肪生成抑制脂肪生成的共同反应抑制剂。我们进行了代谢追踪研究，以确认 c-MYC 和 TOFA 对脂肪生成的影响。我们在体外和体内鉴定了 TOFA 的特异性细胞死亡反应，并证明了移植的淋巴瘤细胞系体内延迟的植入和进展。我们还在原代转基因小鼠模型中观察到 TOFA 给药后 T-ALL 进展延迟。在一组人类细胞系中，我们证明了对 TOFA 治疗作为代谢负担的敏感性，因为在 MYC、RAS 或 BCR-ABL 驱动的淋巴恶性肿瘤中从头脂肪生成普遍趋同。重要的是，在体内非恶性细胞中没有明显观察到细胞死亡。这些研究表明，从头脂肪生成可能是许多淋巴恶性肿瘤的常见生存策略，并且可能是临床上可利用的代谢倾向。这项研究不包括对人类受试者的任何临床干预。