Medical Clinic I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
Medical Clinic III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
Ann Hematol. 2019 Sep;98(9):2063-2072. doi: 10.1007/s00277-019-03756-1. Epub 2019 Jul 16.
Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement.
里戈塞替尼是一种新型多激酶抑制剂，对接受低甲基化药物治疗后进展或复发的高危骨髓增生异常综合征（MDS）患者的白血病祖细胞具有临床活性。由于骨髓微环境在 MDS 发病机制中起重要作用，我们研究了里戈塞替尼对成骨-造血龛内细胞区室的影响。健康的 C57BL/6J 小鼠用里戈塞替尼治疗 3 周后，造血功能受到轻度抑制（血红蛋白和红细胞均减少 16%，p<0.01；白细胞减少 34%，p<0.05；血小板减少 38%，p<0.05），而骨髓中的造血干细胞数量没有差异。脊柱小梁骨量减少（-16%，p=0.05）。这伴随着小梁数量和厚度的降低（分别为-6%和-10%，p<0.05），部分原因是破骨细胞数量和表面的增加（p<0.01）。在 MDS 小鼠模型系统（NHD13）中，里戈塞替尼对骨量的影响较轻。然而，里戈塞替尼并没有进一步加重 NHD13 小鼠的 MDS 相关血细胞减少症。最后，我们在体外测试了里戈塞替尼对人间充质基质细胞（MSC）的作用，结果表明纳米摩尔浓度的细胞活力降低。在里戈塞替尼预处理后，MDS-MSC 的造血支持能力恶化，表现为集落形成单位数量减少，尤其是单核细胞谱系，这进一步支持了里戈塞替尼介导的成骨-造血龛内细胞间通讯紊乱的观点。因此，里戈塞替尼对成骨-造血龛的基质成分具有抑制作用，这可能解释了抗白血病活性与血液学改善缺失之间的分离。
