Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 03 2023
17 03 2023
Historique:
received:
15
07
2022
accepted:
01
03
2023
entrez:
18
3
2023
pubmed:
19
3
2023
medline:
22
3
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36932114
doi: 10.1038/s41467-023-37175-8
pii: 10.1038/s41467-023-37175-8
pmc: PMC10023686
doi:
Substances chimiques
Azacitidine
M801H13NRU
Protein-Lysine 6-Oxidase
EC 1.4.3.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1497Informations de copyright
© 2023. The Author(s).
Références
Blood. 2016 Sep 1;128(9):1246-59
pubmed: 27268087
Arch Stem Cell Ther. 2020 Dec;1(1):23-27
pubmed: 33738462
Cells. 2020 Apr 06;9(4):
pubmed: 32268541
Blood. 2019 Mar 7;133(10):1096-1107
pubmed: 30670446
Conf Proc IEEE Eng Med Biol Soc. 2006;2006:775-8
pubmed: 17946857
Exp Cell Res. 2007 Oct 1;313(16):3616-23
pubmed: 17673200
Oncogene. 2013 Apr 4;32(14):1863-8
pubmed: 22641216
Leukemia. 2019 Jun;33(6):1487-1500
pubmed: 30575819
Biomark Res. 2020 Jun 12;8:20
pubmed: 32537166
Cell Stem Cell. 2021 Apr 1;28(4):637-652.e8
pubmed: 33301706
Blood Adv. 2018 Dec 11;2(23):3447-3461
pubmed: 30518537
Nat Commun. 2021 Oct 25;12(1):6170
pubmed: 34697318
Haematologica. 2017 Dec;102(12):2015-2020
pubmed: 28983059
Clin Transl Med. 2021 Nov;11(11):e572
pubmed: 34841699
N Engl J Med. 2020 Oct 1;383(14):1358-1374
pubmed: 32997910
Int J Hematol. 2019 Dec;110(6):699-708
pubmed: 31637674
Cell Stem Cell. 2014 Jun 5;14(6):824-37
pubmed: 24704494
PLoS Comput Biol. 2014 Aug 07;10(8):e1003665
pubmed: 25102416
Antioxidants (Basel). 2021 Feb 19;10(2):
pubmed: 33669630
Blood Cancer J. 2017 Feb 3;7(2):e525
pubmed: 28157219
Int J Hematol. 2020 Sep;112(3):316-330
pubmed: 32572826
EMBO J. 2010 Aug 18;29(16):2753-68
pubmed: 20717145
Int J Biochem Cell Biol. 2007;39(12):2183-94
pubmed: 17659994
J Biol Chem. 2011 Aug 5;286(31):27630-8
pubmed: 21665949
Leukemia. 2021 Oct;35(10):2936-2947
pubmed: 34002031
Blood. 2011 Nov 24;118(22):5938-46
pubmed: 21926352
Nat Rev Cancer. 2020 May;20(5):285-298
pubmed: 32112045
Sci Adv. 2017 Jan 06;3(1):e1600455
pubmed: 28070554
Am J Hematol. 2013 May;88(5):355-8
pubmed: 23494965
Haematologica. 2020 May;105(5):1189-1200
pubmed: 32241851
Blood. 2010 May 6;115(18):3704-7
pubmed: 20207983
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
Oncogene. 2018 Sep;37(36):4921-4940
pubmed: 29780168
Blood. 2019 Mar 7;133(10):1031-1038
pubmed: 30670448
Leukemia. 2022 Jan;36(1):236-247
pubmed: 34172896
J Biol Chem. 2011 Oct 28;286(43):37196-206
pubmed: 21903580
Nat Commun. 2020 May 15;11(1):2416
pubmed: 32415208
Am J Hematol. 2021 Jan;96(1):145-162
pubmed: 33197049
Blood. 1984 Oct;64(4):922-9
pubmed: 6206904
Nat Methods. 2013 Aug;10(8):788-94
pubmed: 23793238