Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome

•Azacitidine (AZA) inhibits proliferation of myeloid leukemia associated with Down syndrome (ML-DS) cell lines established from relapsed cases.•Transient azacitidine (AZA) treatment impairs the next-generation clonogenic potential of ML-DS.•Comprehensive differential gene expression analysis indicat...

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Veröffentlicht in:Experimental hematology 2024-04, Vol.132, p.104179-104179, Article 104179
Hauptverfasser: Tanaka, Tatsuhiko, Kudo, Ko, Kanezaki, Rika, Yuzawa, Kentaro, Toki, Tsutomu, Okuse, Ryo, Kobayashi, Akie, Sato, Tomohiko, Kamio, Takuya, Terui, Kiminori, Ito, Etsuro
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Sprache:eng
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Zusammenfassung:•Azacitidine (AZA) inhibits proliferation of myeloid leukemia associated with Down syndrome (ML-DS) cell lines established from relapsed cases.•Transient azacitidine (AZA) treatment impairs the next-generation clonogenic potential of ML-DS.•Comprehensive differential gene expression analysis indicates that AZA induces megakaryocytic differentiation in ML-DS.•AZA induces activation of interferon pathway genes without autocrine stimulation. Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2024.104179