To investigate the mechanisms of drug resistance in ALL, we established the resistant cell lines Reh-6MPR (6-MP Resistant cell) and Reh-6TGR (6-TG Resistant cell) by inducing Reh cells with 6-MP or 6-TG, and we found a novel HPRT1 mutation c.495_496insA (p.V165fs) in these two resistant cells by whole exome sequencing. This evidence concerns the gene HPRT1 and acute lymphoblastic leukemia.