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Developmental regulation of myeloid gene expression and demethylation
during ex vivo culture of peripheral blood progenitor cells
M Lubbert, W Brugger, R Mertelsmann and L Kanz
Department of Hematology/Oncology, University of Freiburg Medical Center,
Germany.
Expression of tissue- and development-specific genes is coordinately
regulated during maturation of hematopoietic precursor cells toward
functional, end-stage peripheral blood (PB) cells. To study the expression
and methylation of several myeloid-specific genes during in vitro
differentiation of normal hematopoietic progenitor cells, we used a model
of CD34+ selected PB progenitor cells (PBPCs). PBPCs from six patients with
solid tumors were recruited by standard-dose chemotherapy and subsequent
administration of recombinant granulocyte colony- stimulating factor
(G-CSF). PBPCs were collected and CD34+ cells selected by immunoadsorption
columns using a biotinylated anti-CD34 monoclonal antibody. Enriched cells
contained between 78% and 90% (median, 84%) CD34+ cells as determined by
fluorescence-activated cell sorting analysis. Cell preparations were
cultured in the presence of interleukin-1 beta (IL-1 beta), IL-3, IL-6 and
stem cell factor and with or without G-CSF for various time intervals up to
20 days. Genes for CD34 surface antigen, lysozyme (LZM) and myeloperoxidase
(MPO) were examined by RNA and DNA analyses. A rapid and early
downregulation of CD34 transcripts was observed, with concomitant,
time-dependent upregulation of expression of both the LZM and MPO genes.
These effects were enhanced in the presence of G-CSF. Analysis of the DNA
methylation status at key sites within these genes showed a pattern of
differentiation- and expression-associated demethylation of the LZM gene,
which was also enhanced by G-CSF, and constitutive and unaltered
demethylation at key regions of the CD34 and MPO genes. In conclusion, the
genes for CD34, LZM, and MPO are regulated during in vitro culture of very
immature PBPCs in the presence of stem cell factor, IL-1, IL-3, IL-6; their
effects are enhanced by G-CSF.
Volume 87,
Issue 2,
pp. 447-455,
01/15/1996
Copyright © 1996 by The American Society of Hematology
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