Nature communications · 2023
Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.
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Xu Qingyu, Streuer Alexander, Jann Johann-Christoph, Altrock Eva, Schmitt Nanni, Flach Johanna, Sens-Albert Carla, Rapp Felicitas, Wolf Julia, Nowak Verena, Weimer Nadine, Obländer Julia, Palme Iris, Kuzina Mariia, Jawhar Ahmed, Darwich Ali, Weis Cleo-Aron, Marx Alexander, Wuchter Patrick, Costina Victor, Jäger Evelyn, Sperk Elena, Neumaier Michael, Fabarius Alice, Metzgeroth Georgia, Nolte Florian, Steiner Laurenz, Levkin Pavel A, Jawhar Mohamad, Hofmann Wolf-Karsten, Riabov Vladimir, Nowak Daniel
Аннотация
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.