Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase
| Autor: | Danny V. Jeyaraju, Maryam Alapa, Ann Polonskaia, Alberto Risueño, Prakash Subramanyam, Amit Anand, Kaushik Ghosh, Charalampos Kyriakopoulos, Daiane Hemerich, Rose Hurren, Xiaoming Wang, Marcela Gronda, Aarif Ahsan, Hsiling Chiu, Geethu Thomas, Evan F. Lind, Daniel L Menezes, Aaron D. Schimmer, Patrick R. Hagner, Anita Gandhi, Anjan G. Thakurta |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Haematologica, Vol 109, Iss 4 (2023) |
| Druh dokumentu: | article |
| ISSN: | 0390-6078 1592-8721 |
| DOI: | 10.3324/haematol.2023.283437 |
| Popis: | Oral azacitidine (oral-Aza) treatment results in longer median overall survival (OS) (24.7 vs. 14.8 months in placebo) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy. The dosing schedule of oral-Aza (14 days/28-day cycle) allows for low exposure of Aza for an extended duration thereby facilitating a sustained therapeutic effect. However, the underlying mechanisms supporting the clinical impact of oral-Aza in maintenance therapy remain to be fully understood. In this preclinical work, we explore the mechanistic basis of oral-Aza/extended exposure to Aza through in vitro and in vivo modeling. In cell lines, extended exposure to Aza results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to Aza, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of Aza induces differentiation and depletes CD34+CD38- LSC. Mechanistically, LSC differentiation is driven in part by increased myeloperoxidase (MPO) expression. Inhibition of MPO activity either by using an MPO-specific inhibitor or blocking oxidative stress, a known mechanism of MPO, partly reverses the differentiation of LSC. Overall, our preclinical work reveals novel mechanistic insights into oral-Aza and its ability to target LSC. |
| Databáze: | Directory of Open Access Journals |
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