Background Overexpression of c-Myc is required for the progression of pre-malignant plasma cells in monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cells in multiple myeloma (MM). c-Myc also increases glutamine anaplerosis into the tricarboxylic acid (TCA) cycle within cancer cells. Whether increased glutamine anaplerosis is associated with the progression of pre-malignant to malignant plasma cells is unknown. Methods Human volunteers ( N = 7) and patients with MGUS ( N = 11) and MM ( N = 12) were prospectively recruited to undergo an intravenous infusion of 13 C-labeled glutamine followed by a bone marrow aspiration to obtain bone marrow cells and plasma. Results Despite notable heterogeneity, stable isotope-resolved metabolomics (SIRM) revealed that the mean 13 C-labeled glutamine anaplerosis into the TCA cycle was higher in malignant compared to pre-malignant bone marrow plasma cells relative to the remainder of their paired bone marrow mononuclear cells. RNA sequencing demonstrated a higher relative mRNA expression of c-Myc and glutamine transporters such as ASCT2 and SN2 in malignant compared to pre-malignant bone marrow plasma cells. Finally, higher quantitative levels of TCA cycle intermediates in the bone marrow plasma differentiated MM from MGUS patients. Conclusion Measurement of the in vivo activity of glutamine anaplerosis into the TCA cycle provides novel insight into the metabolic changes associated with the transformation of pre-malignant plasma cells in MGUS to malignant plasma cells in MM. Trial registration NCT03384108 and NCT03119883

中文翻译：

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在人恶性前和恶性克隆浆细胞中谷氨酰胺回补进入 TCA 循环的体内评估

背景 未确定意义的单克隆丙种球蛋白病 (MGUS) 中的恶性前浆细胞向多发性骨髓瘤 (MM) 中的恶性浆细胞进展需要 c-Myc 的过表达。c-Myc 还会增加谷氨酰胺回补到癌细胞内的三羧酸 (TCA) 循环。谷氨酰胺回补增加是否与恶性前浆细胞向恶性浆细胞的进展有关尚不清楚。方法 前瞻性招募人类志愿者 (N = 7) 和 MGUS (N = 11) 和 MM (N = 12) 患者接受 13 C 标记的谷氨酰胺静脉输注，然后进行骨髓穿刺以获得骨髓细胞和等离子体。结果 尽管存在显着的异质性，稳定同位素解析代谢组学 (SIRM) 显示，相对于其配对骨髓单核细胞的其余部分，与恶性前骨髓浆细胞相比，恶性的 13 C 标记谷氨酰胺回补进入 TCA 循环的平均值更高。RNA 测序表明，与恶性前骨髓浆细胞相比，c-Myc 和谷氨酰胺转运蛋白（如 ASCT2 和 SN2）的相对 mRNA 表达更高。最后，骨髓血浆中更高定量水平的 TCA 循环中间体将 MM 与 MGUS 患者区分开来。结论 谷氨酰胺回补对 TCA 循环的体内活性的测量提供了对与 MGUS 中的恶性前浆细胞转化为 MM 中的恶性浆细胞相关的代谢变化的新见解。