Pluto Bioinformatics

GSE152441: Effect of folic acid deprivation on on transcriptome upon OTX treatment

Bulk RNA sequencing

Deciphering the impact of metabolic intervention on response to anticancer therapy represents a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate-cycle enzyme, MTHFR which exhibits reduced-function polymorphisms in about 10% of Caucasians enhance resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples and syngeneic mouse models of AML. Further, this effect is abrogated by supplementation with the MTHFR enzymatic product, CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation, and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and the folate cycle status to exclude patients least likely and nominate those most likely to benefit from MYC-targeting therapies. SOURCE: Camille Lobry (camille.lobry@inserm.fr) - Lobry lab Inserm