Methylation of histones in myeloid leukemias as a potential marker of granulocyte abnormalities
We show that common heterochromatin antigenic protein markers [HPlalpha, -beta, -y and mono-, di-, and trimethylated histone 113 lysine 9 (H3K9)], although present in human blood progenitor CD34(+) cells, differentiated lymphocytes, and monocytes, are absent in neutrophil granulocytes and to large extent, in eosinophils. Monomethylated and in particular, dimethylated H3K9 are present to variable degrees in the granulocytes of chronic myeloid leukemia (CML) patients, without being accompanied by UPl proteins. In patients with an acute phase of CML and in acute rnyeloid leukemia patients, strong methylation of H3K9 and all isoforms of HPl are detected. In chronic forms of CML, no strong correlations among the level of histone methylation, disease progression, and modality of treatment were observed. Histone methylation was found even in "cured" patients without Philadelphia chromosome (Ph) resulting from +(9;22)(q34;q11) BCR/ABL translocation, suggesting an incomplete process of developmentally regulated chromatin remodeling in the granulocytes of these patients. Similarly, reprogramming of leukemia HL-60 cells to terminal differentiation by retinoic acid does not eliminate H3K9 methylation and the presence of UPI isoforms from differentiated granulocytes. Thus, our study shows for the first time that bistone H3 methylation may be changed dramatically during normal cell differentiation. The residual histone H3 methylation in myeloid leukemia cells suggests an incomplete chromatin condensation that may be linked to the leukemia cell proliferation and may be important for the prognosis of disease treatment and relapse.