Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies
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...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
17 March 2023
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| In: |
Nature Communications
Year: 2023, Jahrgang: 14, Pages: 1-17 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-023-37175-8 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-023-37175-8 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-023-37175-8 
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| Verfasserangaben: | Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Eva Altrock, Nanni Schmitt, Johanna Flach, Carla Sens-Albert, Felicitas Rapp, Julia Wolf, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Mariia Kuzina, Ahmed Jawhar, Ali Darwich, Cleo-Aron Weis, Alexander Marx, Patrick Wuchter, Victor Costina, Evelyn Jäger, Elena Sperk, Michael Neumaier, Alice Fabarius, Georgia Metzgeroth, Florian Nolte, Laurenz Steiner, Pavel A. Levkin, Mohamad Jawhar, Wolf-Karsten Hofmann, Vladimir Riabov & Daniel Nowak |
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| 245 | 1 | 0 | |a Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies |c Qingyu Xu, Alexander Streuer, Johann-Christoph Jann, Eva Altrock, Nanni Schmitt, Johanna Flach, Carla Sens-Albert, Felicitas Rapp, Julia Wolf, Verena Nowak, Nadine Weimer, Julia Obländer, Iris Palme, Mariia Kuzina, Ahmed Jawhar, Ali Darwich, Cleo-Aron Weis, Alexander Marx, Patrick Wuchter, Victor Costina, Evelyn Jäger, Elena Sperk, Michael Neumaier, Alice Fabarius, Georgia Metzgeroth, Florian Nolte, Laurenz Steiner, Pavel A. Levkin, Mohamad Jawhar, Wolf-Karsten Hofmann, Vladimir Riabov & Daniel Nowak |
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| 520 | |a 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. | ||
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