Excess Serine from the Microenvironment Caused the Impaired Megakaryopoiesis and Thrombocytopia in Multiple Myeloma

Background: Thrombocytopenia is major complication in a subset of patients with multiple myeloma (MM). However, a lack of detailed studies about the megakaryopoiesis, thrombopoiesis as well as their connections with the survival of patients limits us to explore whether thrombocytopenia could be used as a reliable prognostic factor for MM.

Materials and Methods: In this study, 1393 newly diagnosed MM patients were selected for investigating the potential connection between PLT counts and clinical characteristics including ISS stage, overall survival as well as progression free survival. Besides, 5T33MMvt-KaLwRij mouse model were also used to examine the megakaryopoiesis and thrombopoiesis during disease progression. The proportion and function of different subpopulations of cells including megakaryocytes, megakaryocytic-erythroid progenitors (MEPs), common myeloid progenitors (CMPs) and Lin^-Sca-1⁺c-kit⁺ (LSK) cells were measured both in MM patients and mouse models. Gas chromatography-time-of-flight mass spectrometry (GC-TOFMS)-based metabolomics was used to analyze the metabolites.

Results: Of the 1393 studied patients, 298 cases of MM patients are found with thrombocytopenia at the time of diagnosis. PLT counts were lower both in stage Ⅱ (P<0.01) and Ⅲ patients (P<0.001) than stageⅠpatients. Interesting, we found MM patients with thrombocytopenia had a significantly lower OS (P<0.001) and PFS (P<0.001). In mouse model, we also found PLT counts gradually decreased in peripheral blood during the disease progression (P<0.001). Further analysis demonstrated the proportion and the absolute numbers of megakaryocytes and MEPs were diminished both in mouse and MM patients with thrombocytopenia. PLT counts were negative correlated with the percentage of plasma cells or IgG2b levels (P<0.001), suggesting a potential connection of malignant cells infiltration and thrombocytopenia. In mechanism, metabolomics analysis with BM plasma identified 16 differential metabolites in MM patients with thrombopoiesis (VIP > 1.2, P < 0.05). Among them, serine was observed significantly be elevated in MM mouse and suffice to inhibit the megakaryopoieis and thrombopoiesis in vitro.

Conclusion: PLT counts might be used as a reliable prognostic factor for MM patients since the thrombocytopenia was associated with poor survival in MM patients. The thrombocytopenia in MM might attribute to, at least partially, the inhibition by serine from the microenvironment. Our findings revealed novel mechanism of MM and might eventually shed light on the treatment of MM patients.