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Methotrexate (MTX) is an essential component of ALL treatment.Although the optimal dosage is still discussed, high-dose MTX is commonly used in induction consolidation in childhood ALL treatment protocols.Intracellulary, MTX is converted into poly(y-glutamate) forms (MTXPGs).The ability of cells to accumulate MTXPG (especially long-chain MTXPGs) has been shown to influence treatment response and outcome in childhood ALL.A pathway directed candidate gene approach was used to elucidate genomic determinants of in vivo MTXPG accumulation amongALL subtypes.MTXPG levels were found to differ significantly among the ALL subtypes studied.Expression data showed a significant pattern of 23 folate related genes significantly associated with ALL subtypes and cellular MTXPG accumulation.