Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Geriatric Disorders, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
Nat Commun. 2023 Apr 13;14(1):2093. doi: 10.1038/s41467-023-37699-z.
Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM. Here, we show thrombocytopenia is linked to poor prognosis in MM. In addition, we identify serine, which is released from MM cells into the bone marrow microenvironment, as a key metabolic factor that suppresses megakaryopoiesis and thrombopoiesis. The impact of excessive serine on thrombocytopenia is mainly mediated through the suppression of megakaryocyte (MK) differentiation. Extrinsic serine is transported into MKs through SLC38A1 and downregulates SVIL via SAM-mediated tri-methylation of H3K9, ultimately leading to the impairment of megakaryopoiesis. Inhibition of serine utilization or treatment with TPO enhances megakaryopoiesis and thrombopoiesis and suppresses MM progression. Together, we identify serine as a key metabolic regulator of thrombocytopenia, unveil molecular mechanisms governing MM progression, and provide potential therapeutic strategies for treating MM patients by targeting thrombocytopenia.
血小板减少症是多发性骨髓瘤（MM）患者亚群的主要并发症之一。然而，对于其在 MM 中的发生发展及其意义，人们知之甚少。在这里，我们发现血小板减少症与 MM 的不良预后相关。此外，我们发现丝氨酸是一种从 MM 细胞释放到骨髓微环境中的关键代谢因子，可抑制巨核细胞（MK）分化和血小板生成。过多丝氨酸对血小板减少症的影响主要通过抑制 MK 分化来介导。外源性丝氨酸通过 SLC38A1 转运到 MK 中，并通过 SAM 介导的 H3K9 三甲基化下调 SVIL，最终导致巨核细胞生成受损。抑制丝氨酸利用或用 TPO 治疗可增强巨核细胞生成和血小板生成，并抑制 MM 进展。综上所述，我们确定丝氨酸是血小板减少症的关键代谢调节剂，揭示了控制 MM 进展的分子机制，并通过针对血小板减少症为治疗 MM 患者提供了潜在的治疗策略。
