Author:
Jeyaraju Danny V.,Alapa Maryam,Polonskaia Ann,Risueño Alberto,Subramanyam Prakash,Anand Amit,Ghosh Kaushik,Kyriakopoulos Charalampos,Hemerich Daiane,Hurren Rose,Wang Xiaoming,Gronda Marcela,Ahsan Aarif,Chiu Hsiling,Thomas Geethu,Lind Evan F.,Menezes Daniel L,Schimmer Aaron D.,Hagner Patrick R.,Gandhi Anita,Thakurta Anjan G.
Abstract
Oral azacitidine (Oral-Aza; CC-486) 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 azacitidine 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 azacitidine through in vitro and in vivo modeling. In cell lines, extended exposure to azacitidine results in sustained DNMT1 loss, leading to durable hypomethylation, and gene expression changes. In mouse models, extended exposure to azacitidine, preferentially targets immature leukemic cells. In leukemic stem cell (LSC) models, the extended dose of azacitidine induces differentiation and depletes CD34+CD38- LSCs. 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 LSCs. Overall, our pre-clinical work reveals novel mechanistic insights into oral-Aza and its ability to target leukemic stem cells.
Publisher
Ferrata Storti Foundation (Haematologica)
Cited by
2 articles.
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