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

Author

Listed:
  • 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
    Karlsruhe Institute of Technology)

  • Mohamad Jawhar

    (Heidelberg University)

  • Wolf-Karsten Hofmann

    (Heidelberg University)

  • Vladimir Riabov

    (Heidelberg University)

  • Daniel Nowak

    (Heidelberg University)

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.

Suggested Citation

  • 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 & , 2023. "Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37175-8
    DOI: 10.1038/s41467-023-37175-8
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    References listed on IDEAS

    as
    1. Johann-Christoph Jann & Maximilian Mossner & Vladimir Riabov & Eva Altrock & Nanni Schmitt & Johanna Flach & Qingyu Xu & Verena Nowak & Julia Obländer & Iris Palme & Nadine Weimer & Alexander Streuer , 2021. "Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    2. Ozge Saatci & Aysegul Kaymak & Umar Raza & Pelin G. Ersan & Ozge Akbulut & Carolyn E. Banister & Vitali Sikirzhytski & Unal Metin Tokat & Gamze Aykut & Suhail A. Ansari & Hayriye Tatli Dogan & Mehmet , 2020. "Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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