Abstract: OBJECTIVE To study the mechanism of killing acute lymphoblastic leukemia(ALL) cells by targeting small molecule peptides that inhibit ERG.METHODS CellTiter-Glo^® cell viability assay kit was used to detect the effect of different concentrations of small molecule polypeptides on the proliferation and viability of ERG-positive ALL cell lines; Annexin V/PI double staining method was used to detect the apoptosis induction of molecular polypeptides on ERG-positive ALL cell lines. The nude mouse subcutaneous tumor model was used to evaluate the killing effect of small-molecule polypeptides on ERG-positive ALL cell lines in vivo; Western blotting detected the proteasome inhibitors on the degradation of ERG by small-molecule polypeptides; lentiviral-packaged plasmid transfected into ALL cell lines, which interfered with the expression of ERG, and observed its effect on c-Myc; lentiviral-packaged plasmid transfected into ALL cell lines to silence c-Myc expression, and observed its effect on nesting factor GDF15 expression. RESULTS Small molecule peptides targeting ERG degradation could kill ALL cell lines in vitro and in vivo; the expression of GDF15 was significantly inhibited in the cell lines that knocked down the expression of ERG and c-Myc by plasmid transfection. CONCLUSION This study clarifies that small molecule polypeptides have the effect of killing ERG-positive ALL cells in vitro and in vivo. They inhibit the expression of ERG through proteasomal degradation, and may inhibit the nesting factor GDF15 through c-Myc, thereby killing ERG-positive ALL cell lines.