Induction of differentiation of HL-60 cells along the monocytic pathway by 5-methyltetrahydrofolate

Many compounds of different chemical structure can induce the HL-60 cell line to differentiate along the monocytic or granulocytic pathway, but the mechanism(s) of differentiation by these agents is not known. Experimental evidence suggests that DNA and/or membrane phospholipid transmethylation reactions may be of importance. Based on this background, we have studied the effects of various concentrations of (dl)-5-methyltetrahydrofolate (mTHF), a folate coenzyme involved in transmethylation reactions, on differentiation of HL-60 cells. Differentiation along the monocytic pathway was evidenced in kinetic, functional, cytochemical and immunophenotypical studies when cells were treated with high-dose (dl)-mTHF (1 x 10(-3)M). Some hypotheses on the mechanism(s) of (dl)-mTHF induced HL-60 cell differentiation are discussed with particular regard to a possible enhancement of lipid or DNA methylation via methionine formation by the (l) form or to inhibition of folate-dependent metabolism by the unnatural (d) form, hence of purine and thymine nucleotide synthesis.