Treatment with 5-Azacytidine Accelerates Acute Promyelocytic Leukemia Leukemogenesis in a Transgenic Mouse Model

Abstract

A key oncogenic force in acute promyelocytic leukemia (APL) is the ability of the promyelocytic leukemia-retinoic acid receptor α (PML-RARA) oncoprotein to recruit transcriptional repressors and DNA methyltransferases at retinoic acid-responsive elements. Pharmacological doses of retinoic acid relieve transcriptional repression inducing terminal differentiation/apoptosis of the leukemic blasts. APL blasts often harbor additional recurrent chromosomal abnormalities, and significantly, APL prevalence is increased in Latino populations. These observations suggest that multiple genetic and environmental/dietary factors are likely implicated in APL. We tested whether dietary or targeted chemopreventive strategies relieving PML-RARA transcriptional repression would be effective in a transgenic mouse model. Surprisingly, we found that 1) treatment with a demethylating agent, 5-azacytidine, results in a striking acceleration of APL; 2) a high fat, low folate/choline-containing diet resulted in a substantial but nonsignificant APL acceleration; and 3) all-trans retinoic acid (ATRA) is ineffective in preventing leukemia and results in ATRA-resistant APL. Our findings have important clinical implications because ATRA is a drug of choice for APL treatment and indicate that global demethylation, whether through dietary manipulations or through the use of a pharmacologic agent such as 5-azacytidine, may have unintended and detrimental consequences in chemopreventive regimens.

SERS-Based Assessment of MRD in Acute Promyelocytic Leukemia?

“…Scaglioni et al also report up-regulation of Birc1e (IAP inhibitor that counteracts cell death), Sept9 (growth suppressor), and angiopoietin-like 4 (pro-metastatic gene). All this gene alteration implies that 5-Azacytidine, through its epigenetic modifications, can promote leukemogenesis ( 68 ), which is surprising given the fact that according to previous studies, PML/RARA-induced hypermethylation and gene silencing is an important mechanism in APL pathogenesis ( 68 ).…”

“…When looking at mice transplanted with cells collected from the bone marrow of preleukemic APL transgenic mice, after treatment with 5-Azacytidine, the mice developed a marked acceleration of leukemogenesis ( 68 ). Altered expression of several genes is reported in the 5-Azacytidine-treated group.…”