TY - JOUR
T1 - Extended exposure to low doses of azacitidine induces differentiation of leukemic stem cells through activation of myeloperoxidase
AU - Jeyaraju, Danny V.
AU - Alapa, Maryam
AU - Polonskaia, Ann
AU - Risueño, Alberto
AU - Subramanyam, Prakash
AU - Anand, Amit
AU - Ghosh, Kaushik
AU - Kyriakopoulos, Charalampos
AU - Hemerich, Daiane
AU - Hurren, Rose
AU - Wang, Xiaoming
AU - Gronda, Marcela
AU - Ahsan, Aarif
AU - Chiu, Hsiling
AU - Thomas, Geethu
AU - Lind, Evan F.
AU - Menezes, Daniel L.
AU - Schimmer, Aaron D.
AU - Hagner, Patrick R.
AU - Gandhi, Anita
AU - Thakurta, Anjan G.
N1 - Publisher Copyright:
© 2024 Ferrata Storti Foundation. All rights reserved.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
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U2 - 10.3324/haematol.2023.283437
DO - 10.3324/haematol.2023.283437
M3 - Article
C2 - 37941406
AN - SCOPUS:85181962706
SN - 0390-6078
VL - 109
SP - 1082
EP - 1094
JO - Haematologica
JF - Haematologica
IS - 4
ER -