Choline-dependent methionine metabolism supports leukemia progression

Tumor cells must occupy and thrive in a competitive microenvironment marked by limited metabolites, including essential amino acids like methionine. Using a leukemia suppression model and CRISPR screening, we found that the choline transporter SLC44A1 is overexpressed in leukemia patients and impacts leukemogenesis. Choline is an important nutrient for membrane synthesis and less commonly contributes to the methionine cycle. A metabolic analysis demonstrated that metabolites of the methionine pathway are significantly elevated in leukemic cells. Surprisingly, dietary restriction of methionine accelerated leukemogenesis in vivo. Choline can serve as an alternative source for methionine via the enzymatic activity of CHDH and BHMT. Under restrictive methionine conditions, BHMT and CHDH are significantly upregulated. In vivo, BHMT and CHDH are necessary for leukemia progression where they utilize choline as an alternative source to satisfy increased methionine demand. This pathway represents a vulnerability in cancer cells that may be exploited for therapeutic intervention.