Inhibition of Lysyl Oxidases Synergizes with 5-azacytidine to Restore Erythropoiesis in Myelodysplastic and Myeloid Malignancies

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Mar 18

PMID 36932114

Authors

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 Oblander

Iris Palme

Mariia Kuzina

Ahmed Jawhar

Ali Darwich

Cleo-Aron Weis

Alexander Marx

Patrick Wuchter

Victor Costina

Evelyn Jager

Elena Sperk

Michael Neumaier

Alice Fabarius

Georgia Metzgeroth

Florian Nolte

Laurenz Steiner

Pavel A Levkin

Mohamad Jawhar

Wolf-Karsten Hofmann

Vladimir Riabov

Daniel Nowak

Affiliations

Soon will be listed here.

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.

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