Hematopoietic stem and progenitor cell differentiation are blocked in acute myeloid leukemia
(AML) resulting in cytopenias and a high risk of death. Most patients with AML become resistant
to treatment due to lack of effective cytotoxic and differentiation promoting compounds. High
MN1 expression confers poor prognosis to AML patients and induces resistance to cytarabine and alltrans-retinoic acid (ATRA) induced differentiation. Using a high-throughput drug screening, we identified
the dihydrofolate reductase (DHFR) antagonist pyrimethamine to be a potent inducer of apoptosis
and differentiation in several murine and human leukemia cell lines. Oral pyrimethamine treatment
was effective in two xenograft mouse models and specifically targeted leukemic cells in human
AML cell lines and primary patient cells, while CD34+ cells from healthy donors were unaffected.
The antileukemic effects of PMT could be partially rescued by excess folic acid, suggesting an oncogenic
function of folate metabolism in AML. Thus, our study identifies pyrimethamine as a candidate
drug that should be further evaluated in AML treatment.