Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, PA, USA.
Blood. 2010 Jan 21;115(3):605-14. doi: 10.1182/blood-2009-05-221077. Epub 2009 Nov 25.
The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs down-regulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma.
免疫调节药物（IMiDs）来那度胺和泊马度胺在多发性骨髓瘤患者中产生高反应率，但 IMiDs 在多发性骨髓瘤中的使用与中性粒细胞减少症和静脉血栓栓塞（VTE）风险增加有关，其机制尚不清楚。我们表明，IMiDs 下调 PU.1，这是一种在体外和接受来那度胺治疗的患者中参与粒细胞分化的关键转录因子。PU.1 的缺失导致短暂的成熟停滞，伴有幼稚髓样前体在骨髓中的积累，随后出现中性粒细胞减少症。早幼粒细胞的积累导致储存于早幼粒细胞嗜天青颗粒中的血小板聚集激动剂组织蛋白酶 G 水平升高。随后，组织蛋白酶 G 水平升高可能会增加 VTE 的风险。据我们所知，这是第一项研究 IMiD 诱导的中性粒细胞减少症和多发性骨髓瘤中 VTE 风险增加的潜在机制的报告。
