Excessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma

Chunmei Kuang, Meijuan Xia, Gang An, CuiCui Liu, Cong Hu, Jingyu Zhang, Zhenhao Liu, Bin Meng, Pei Su, Jiliang Xia, Jiaojiao Guo, Yinghong Zhu, Xing Liu, Xuan Wu, Yi Shen, Xiangling Feng, Yanjuan He, Jian Li, Lugui Qiu, Jiaxi Zhou () and Wen Zhou ()
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Chunmei Kuang: Central South University
Meijuan Xia: Chinese Academy of Medical Sciences & Peking Union Medical College
Gang An: Chinese Academy of Medical Sciences & Peking Union Medical College
CuiCui Liu: Chinese Academy of Medical Sciences & Peking Union Medical College
Cong Hu: Central South University
Jingyu Zhang: Central South University
Zhenhao Liu: Central South University
Bin Meng: Central South University
Pei Su: Chinese Academy of Medical Sciences & Peking Union Medical College
Jiliang Xia: Central South University
Jiaojiao Guo: Central South University
Yinghong Zhu: Central South University
Xing Liu: Central South University
Xuan Wu: Central South University
Yi Shen: Central South University
Xiangling Feng: Central South University
Yanjuan He: Central South University
Jian Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Lugui Qiu: Chinese Academy of Medical Sciences & Peking Union Medical College
Jiaxi Zhou: Chinese Academy of Medical Sciences & Peking Union Medical College
Wen Zhou: Central South University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37699-z

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