Reversal of p15/INK4b hypermethylation in AML1/ETO-positive and -negative myeloid leukemia cell lines.

摘要: Abstract In vitro and in vivo, myeloid leukemic preleukemic cells exhibit variable sensitivity to the antiproliferative proapoptotic effects induced already at low concentrations of DNA methyltransferase (DNMT) inhibitors. The molecular mechanisms underlying this blasts azanucleosides such as 5-azacytidine 5-aza-2′-deoxycytidine (DAC) may involve modifier specific fusion proteins AML1/ETO. cyclin-dependent kinase inhibitor p15 / INK4b is one potential target demethylating activity AML MDS where it frequently silenced by hypermethylation. To study DAC leukemia cells, we chose cell lines Kasumi-1 (expressing AML1/ETO), KG-1 KG-1a (both AML1/ETO-negative) all which a highly methylated gene. Treatment with resulted dose-dependent regional demethylation KG-1, but only modest degree cells. Demethylation was associated induction p15/INK4b protein expression. Growth-inhibitory significantly higher than sensitization cooperating effect All-trans retinoic acid histone deacetylase (HDAC) Trichostatin A observed. DAC-induced growth inhibition apoptosis were enhanced when AML1/ETO conditionally expressed AML1/ETO-negative U-937 conclusion, hypomethylation reactivation are among events arrest apoptosis. Further studies epigenotype inhibitors DNMTs HDACs appear warranted.