Methylation of histones in myeloid leukemias as a potential marker of granulocyte abnormalities.
We show that common heterochromatin antigenic protein markers [HP1alpha, -beta, -gamma and mono-, di-, and trimethylated histone H3 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 HP1 proteins. In patients with an acute phase of CML and in acute myeloid leukemia patients, strong methylation of H3K9 and all isoforms of HP1 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 HP1 isoforms from differentiated granulocytes. Thus, our study shows for the first time that histone 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.
Lukásová
Emilie
E
Institute of Biophysics, Academy of Sciences of the Czech Republic, Královopolská 135, 612 65 Brno, Czech Republic.
Koristek
Zdenek
Z
Falk
Martin
M
Kozubek
Stanislav
S
Grigoryev
Sergei
S
Kozubek
Michal
M
Ondrej
Vladan
V
Kroupová
Iva
I
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D018450:Disease Progression; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology*; D018922:HL-60 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008875:Middle Aged; D014212:Tretinoin / Q000494:pharmacology
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C000715594:CBX5 protein, human; D002843:Chromatin; D006657:Histones; D000090266:Chromobox Protein Homolog 5; D014212:Tretinoin