Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies

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 () and Daniel Nowak ()
Additional contact information
Qingyu Xu: Heidelberg University
Alexander Streuer: Heidelberg University
Johann-Christoph Jann: Heidelberg University
Eva Altrock: Heidelberg University
Nanni Schmitt: Heidelberg University
Johanna Flach: Heidelberg University
Carla Sens-Albert: Heidelberg University
Felicitas Rapp: Heidelberg University
Julia Wolf: Heidelberg University
Verena Nowak: Heidelberg University
Nadine Weimer: Heidelberg University
Julia Obländer: Heidelberg University
Iris Palme: Heidelberg University
Mariia Kuzina: Karlsruhe Institute of Technology
Ahmed Jawhar: Heidelberg University
Ali Darwich: Heidelberg University
Cleo-Aron Weis: Heidelberg University
Alexander Marx: Heidelberg University
Patrick Wuchter: Heidelberg University
Victor Costina: Heidelberg University
Evelyn Jäger: Heidelberg University
Elena Sperk: Heidelberg University
Michael Neumaier: Heidelberg University
Alice Fabarius: Heidelberg University
Georgia Metzgeroth: Heidelberg University
Florian Nolte: Heidelberg University
Laurenz Steiner: Heidelberg University
Pavel A. Levkin: Karlsruhe Institute of Technology
Mohamad Jawhar: Heidelberg University
Wolf-Karsten Hofmann: Heidelberg University
Vladimir Riabov: Heidelberg University
Daniel Nowak: Heidelberg University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37175-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37175-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37175-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().