Iron is required for in vitro differentiation of both myeloid cell lines and primary CD34 cells. This iron requirement has been linked to the transcriptional induction of the cyclin dependent kinase inhibitor gene, p21WAF1/CIP1 (
Induction of differentiation in HL-60 cells by PMA was accompanied by complex alterations of Sp1 and Sp3 binding to the p21 promoter.
Iron deprivation disrupted the pattern of Sp1 and Sp3 binding induced by PMA.
Iron deprivation did not inhibit p300 recruitment or histone acetylation at the p21 promoter.
Taken together with the observed inhibition by mithramycin of both p21 expression and cell differentiation these results indicate that Sp family interactions with the p21 promoter are required for HL-60 cell differentiation and that these interactions are iron-dependent. Disruption of these interactions by iron deprivation blocks p21 expression and HL-60 cell differentiation. The precise molecular mechanism influenced by iron deprivation remains unknown but does not involve effects on histone acetylation.