Figure 6 |. Reversal of chemotherapy resistance by BCL2 inhibition.

a, Response of ALL patient-derived xenografts treated ex vivo with different chemotherapeutic drugs in combination with ABT199. Bars indicate relative cell viability compared with vehicle treated controls. b-f, Response of B-ALL 37R patient-derived xenografts treated in vivo with vehicle, single-agent ABT199, combinatorial chemotherapy or ABT199 with combinatorial chemotherapy. Panel b shows spleens following acute treatment and the quantification of spleen weights represented as bar graphs. Bars in c show spleen cell counts, while bars in d represent the percentage of human-CD45⁺ cells in the spleen following the indicated treatment arm. Bars in e show femoral bone marrow cell counts, while bars in f represent the percentage of human-CD45⁺ cells in the bone marrow following the indicated treatment arm. g, Schematic representation of the generation and experimental therapeutic treatment of a APOBEC3A-mutagenized relapsed ALL mouse model and experimental therapeutics. h, Immunofluorescence analysis of APOBEC3A subcellular localization and DNA damage (γH2AX) in vehicle and 4OH-tamoxifen (4OH-TMX)-treated ΔE-NOTCH1 APOBEC3A-ERT2 ALL cells. i, Quantification of γH2AX foci in vehicle and 4OH-TMX-treated ΔE-NOTCH1 APOBEC3A-ERT2 ALL cells. j, Survival curves of mice bearing ΔE-NOTCH1 APOBEC3A-ERT2-mutagenized allografts treated with either vehicle (black) or combinatorial chemotherapy (survival in chemotherapy treated primary tumor in blue, survival in chemotherapy treated relapsed tumor in red). Gray bars indicate the duration of treatment. k, Survival curves of mice bearing APOBEC3A-ERT2-mutagenized relapsed allografts treated with either vehicle, single-agent ABT199, combinatorial chemotherapy or ABT199 plus combinatorial chemotherapy. Gray bars indicated the duration of treatment.