State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China.
Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
Sci Rep. 2020 Nov 25;10(1):20508. doi: 10.1038/s41598-020-77450-y.
Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.
贫血是骨髓瘤最常见的并发症，与更差的临床结局相关。虽然骨髓瘤细胞对骨髓的替代被广泛认为是贫血的一种机制，但确切的过程尚未完全理解。我们的 1363 名骨髓瘤患者的大型队列中，超过 50%的患者在诊断时存在中度或重度贫血。贫血与骨髓中骨髓瘤细胞浸润呈正相关，且与患者预后更差相关。骨髓中骨髓瘤细胞的浸润影响 HSPC 的数量和红细胞分化。红细胞生成的主要调节因子 GATA1 和 KLF1 在骨髓瘤 HSPC 中明显下调。然而，趋化因子 CCL3 的编码基因表达明显上调。骨髓瘤患者骨髓血浆中的 CCL3 升高进一步通过激活 CCL3/CCR1/p38 信号通路抑制 HSPC 的红细胞生成，并抑制 GATA1 表达。用 CCR1 拮抗剂治疗可有效恢复 GATA1 表达并挽救 HSPC 中的红细胞生成。骨髓瘤细胞浸润导致 BM 中 CCL3 的表达升高，通过下调 HSPC 中的 GATA1 水平抑制 HSPC 的红细胞生成，从而导致贫血。因此，我们的研究表明，靶向 CCL3 可能是一种治疗贫血和改善骨髓瘤患者生存的潜在策略。
