Figure 7.
Venetoclax effectively suppresses in vivo tumor progression and overcomes menin inhibitor resistance in KMT2A-r leukemia with PCGF1 deficiency. (A) Schematic showing the transplantation of MLL-AF6 murine AML cells into recipient mice, followed by a 4-week continuous oral treatment starting 5 days after transplantation, using either vehicle control or venetoclax at 20 mg/kg per day. (B) WBC counts in peripheral blood of indicated cohorts, measured 21 days after transplantation. (C) Kaplan-Meier survival curve of mice after transplantation of MLL-AF6 murine AML cells expressing the indicated sgRNAs. The P values were calculated by log-rank test. (D) Schematic showing the transplantation of human MV4-11 MLL-AF4 AML cells into recipient mice, followed by a 7-day continuous oral treatment starting 5 days posttransplantation, using either vehicle control or venetoclax at 75 mg/kg per day. (E) Bar plot showing the percentages of human CD45+ cells in the peripheral blood of indicated cohorts measured 12 days after transplantation. (F) Kaplan-Meier survival curve of mice after transplantation of human MV4-11 AML cells expressing indicated sgRNAs. The P values were calculated by the log-rank test. (G) Schematic showing the transplantation of MLL-AF6 murine AML cells into recipient mice, followed by a 4-week continuous oral treatment starting 5 days after transplantation, using a vehicle control, VTP50469 at 60 mg/kg per day (twice daily ), venetoclax at 20 mg/kg per day, or a combination of VTP50469 and venetoclax. (H-I) The Kaplan-Meier survival curve of mice after transplantation of MLL-AF6 murine AML cells expressing sgRNAs targeting Luc (H) and Pcgf1 (I). The P values were calculated by the log-rank test. (J) Schematic of the competitive growth assay. Primary AML cells were infected with Cas9-EGFP–linked sgRNAs and treated with DMSO, VTP50469, venetoclax, or a combination of both compounds for 10 days, followed by flow cytometry measurement of EGFP+ cells. (K-L) Bar plot showing the relative enrichment of sgRNA+ cells in 2 independent AML primary samples. The percentages of sgRNA+ cells in each treatment were normalized to the DMSO treatment control. (M) Dose-response curves showing viabilities of parental and 2 independent VTP50469-resistant OCI-AML2 (left) and MOLM-13 (right) cells after 9-day and 6-day treatments of VTP50469, respectively. (N) Western blot showing the protein levels of PRC1.1 members PCGF1, BCOR, and RYBP in parental and VTP50469-resistant OCI-AML2 and MOLM-13 cells. Relative FCs in protein levels are labeled below. (O) Dose-response curves showing viabilities of parental and VTP50469-resistant OCI-AML2 (left) and MOLM-13 (right) cells after 6-day and 3-day treatment of venetoclax, respectively. GFP, green fluorescent protein; n.s., not significant; Par, parental; Re, menin inhibitor resistant line; WBC, white blood cells; ∗P < .05; ∗∗P < .01; ∗∗∗P < .001.

Venetoclax effectively suppresses in vivo tumor progression and overcomes menin inhibitor resistance in KMT2A-r leukemia with PCGF1 deficiency. (A) Schematic showing the transplantation of MLL-AF6 murine AML cells into recipient mice, followed by a 4-week continuous oral treatment starting 5 days after transplantation, using either vehicle control or venetoclax at 20 mg/kg per day. (B) WBC counts in peripheral blood of indicated cohorts, measured 21 days after transplantation. (C) Kaplan-Meier survival curve of mice after transplantation of MLL-AF6 murine AML cells expressing the indicated sgRNAs. The P values were calculated by log-rank test. (D) Schematic showing the transplantation of human MV4-11 MLL-AF4 AML cells into recipient mice, followed by a 7-day continuous oral treatment starting 5 days posttransplantation, using either vehicle control or venetoclax at 75 mg/kg per day. (E) Bar plot showing the percentages of human CD45+ cells in the peripheral blood of indicated cohorts measured 12 days after transplantation. (F) Kaplan-Meier survival curve of mice after transplantation of human MV4-11 AML cells expressing indicated sgRNAs. The P values were calculated by the log-rank test. (G) Schematic showing the transplantation of MLL-AF6 murine AML cells into recipient mice, followed by a 4-week continuous oral treatment starting 5 days after transplantation, using a vehicle control, VTP50469 at 60 mg/kg per day (twice daily ), venetoclax at 20 mg/kg per day, or a combination of VTP50469 and venetoclax. (H-I) The Kaplan-Meier survival curve of mice after transplantation of MLL-AF6 murine AML cells expressing sgRNAs targeting Luc (H) and Pcgf1 (I). The P values were calculated by the log-rank test. (J) Schematic of the competitive growth assay. Primary AML cells were infected with Cas9-EGFP–linked sgRNAs and treated with DMSO, VTP50469, venetoclax, or a combination of both compounds for 10 days, followed by flow cytometry measurement of EGFP+ cells. (K-L) Bar plot showing the relative enrichment of sgRNA+ cells in 2 independent AML primary samples. The percentages of sgRNA+ cells in each treatment were normalized to the DMSO treatment control. (M) Dose-response curves showing viabilities of parental and 2 independent VTP50469-resistant OCI-AML2 (left) and MOLM-13 (right) cells after 9-day and 6-day treatments of VTP50469, respectively. (N) Western blot showing the protein levels of PRC1.1 members PCGF1, BCOR, and RYBP in parental and VTP50469-resistant OCI-AML2 and MOLM-13 cells. Relative FCs in protein levels are labeled below. (O) Dose-response curves showing viabilities of parental and VTP50469-resistant OCI-AML2 (left) and MOLM-13 (right) cells after 6-day and 3-day treatment of venetoclax, respectively. GFP, green fluorescent protein; n.s., not significant; Par, parental; Re, menin inhibitor resistant line; WBC, white blood cells; ∗P < .05; ∗∗P < .01; ∗∗∗P < .001.

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