限制性反应率和经常性复发是使用低甲基化剂治疗骨髓增生异常综合症时存在的问题，因此急需改善治疗方法。在本研究中，我们将5-氮杂胞苷（5-AZA）与全精氧化酶抑制剂PXS-5505相结合，证明了替代治疗方法对于20/31例（65％）的MN患者造血干细胞和祖细胞的红细胞分化有着优越的修复作用，而单独使用5-AZA仅有9/31例（29％）有效。这种效果需要造血干细胞直接接触骨髓基质成分，并且取决于积分素信号。我们在雌性NOD-Scid-IL2Rγnull（NSG）小鼠的基质依赖骨髓异种移植模型中进一步验证了这些结果，在这个模型中我们演示了对于同种克隆的强制性减少、疾病扩展的显著减轻和脾脏大小的正常化。总体而言，这些结果为研究5-AZA与PXS-5505联合治疗的临床有效性提供了强有力的理论依据，特别适用于贫血型的MN。© 2023年作者。

Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.© 2023. The Author(s).