Disorder Histone Methylation In Acute Leukemia And The Correction By Phenylhexyl Isothiocyanate

OBJECTIVE: To investigate the aberrant of covalent methylation of histones in acute leukemia and phenylhexyl isothiocyanate (PHI)modulated histone methylation of lysine 4 and 9 in patients with acute leukemia. The nature of the disorder in patients with acute leukemia, regarding the status and level of histone methylated H3K4 and H3K9 has not been clearly presented. To study the effect of PHI on the proliferation of primary acute leukemia cells.METHODS: In this study, we examined the histone methylation of the mononuclear cells from nineteen patients of primary untreated acute leukemias. Patient cells from eight acute leukemia were further exposed in culture to PHI, a HDAC inhibitor that has minimal apoptotic effect on normal cells, TSA, a typical of histone deacetylases inhibitor, and 5-AZa, a DNA demethylase. The methylation of histones H3K4 and H3K9 were determined by Western blot. Cell cycle was measured by flow cytometry.RESULTS: The histone methylation of H3K4 was virtually undetectable or significantly lower and hisotne methylation of H3K9 was significantly higher in acute leukemias, as compared to the mononuclear cells from individuals without leukemia. This disorder was consistent among all the nineteen patients examined. Histone methylation of H3K4 was significantly up-regulated and histone methylation of H3K9 was down-regulation in the presence of PHI, to the level as in the normal cells. PHI can restrain primary acute leukemia mononuclear cell growing by arresting cell cycle in G2/M phase and inhibiting cells in S phase.CONCLUSION:: Disorder of histone methylation may represent a marker of acute leukemia for an aberrant post-translational modification of histones and chromatin structure condensation. It could be a epigenetic pathogenesis in acute leukemia. PHI, a HDAC inhibitor, might represent targeted agents for correcting the disorder of methylation. PHI can restrain primary acute leukemia cells growth and may be a new antineoplastic drug. It warrant further experimentation as potential epigenetic regulators for preventing the progression of leukemia.