Figure 4.
Figure 4. BETP-PROTAC ARV-771 is more potent than BETi OTX015 in reducing the in vivo AML burden and improving survival of NSG mice engrafted with luciferase-transduced mtRUNX1 expressing AML cells. (A-C) Mono-Mac-1 and OCI-AML5 cells were treated with the indicated concentrations of BETP-PROTAC ARV-771, BET inhibitor JQ1 or the inactive R-JQ1, or BET inhibitor OTX015 for 48 hours. The percentage of annexin V–positive apoptotic cells were determined by using flow cytometry. (D) NSG mice were infused with luciferase-expressing OCI-AML5 cells and monitored for 7 days. Engraftment of leukemia was documented by bioluminescent imaging. Mice were then treated for 2 weeks with vehicle, OTX015, or ARV-771 as indicated. Mice were then imaged by using a Xenogen camera to determine treatment efficacy. Total flux (photons/second) in vehicle-, OTX015-, or ARV-771–treated mice as determined by bioluminescent imaging. *Total photon counts that were significantly less in the OTX015- and ARV-771–treated mice compared with the vehicle-treated mice (*P < .05, ***P < .005). (E) Kaplan-Meier survival plot of the in vivo activity of OTX015 or ARV-771 against OCI-AML5-Luc xenografts treated for 3 weeks in NSG mice. Significance between OTX015- and ARV-771–treated vs vehicle-treated mice was determined by using a Mantel-Cox rank sum test. (F) NSG mice were infused with luciferase-expressing Mono-Mac-1 cells transduced with doxycycline (DOX)-inducible RUNX1 shRNA and monitored for 4 days. Mice were imaged to document engraftment of leukemia and then treated with vehicle, 10 mg/kg of DOX, and/or OTX015 as indicated for 2 weeks. Mice were imaged with a Xenogen camera, and total photon counts were recorded. *Indicates total flux (photons/second) that were significantly less in the RUNX1 shRNA and RUNX1 shRNA + OTX015-treated mice compared with the vehicle-treated mice (**P < .01). (G) Kaplan-Meier survival plot of the in vivo activity of DOX and/or OTX015 against Mono-Mac-1/GFP-Luc-i-sh-RUNX1 xenografts in NSG mice. Significance between vehicle and DOX and/or OTX015 was determined by using a Mantel-Cox rank sum test.

BETP-PROTAC ARV-771 is more potent than BETi OTX015 in reducing the in vivo AML burden and improving survival of NSG mice engrafted with luciferase-transduced mtRUNX1 expressing AML cells. (A-C) Mono-Mac-1 and OCI-AML5 cells were treated with the indicated concentrations of BETP-PROTAC ARV-771, BET inhibitor JQ1 or the inactive R-JQ1, or BET inhibitor OTX015 for 48 hours. The percentage of annexin V–positive apoptotic cells were determined by using flow cytometry. (D) NSG mice were infused with luciferase-expressing OCI-AML5 cells and monitored for 7 days. Engraftment of leukemia was documented by bioluminescent imaging. Mice were then treated for 2 weeks with vehicle, OTX015, or ARV-771 as indicated. Mice were then imaged by using a Xenogen camera to determine treatment efficacy. Total flux (photons/second) in vehicle-, OTX015-, or ARV-771–treated mice as determined by bioluminescent imaging. *Total photon counts that were significantly less in the OTX015- and ARV-771–treated mice compared with the vehicle-treated mice (*P < .05, ***P < .005). (E) Kaplan-Meier survival plot of the in vivo activity of OTX015 or ARV-771 against OCI-AML5-Luc xenografts treated for 3 weeks in NSG mice. Significance between OTX015- and ARV-771–treated vs vehicle-treated mice was determined by using a Mantel-Cox rank sum test. (F) NSG mice were infused with luciferase-expressing Mono-Mac-1 cells transduced with doxycycline (DOX)-inducible RUNX1 shRNA and monitored for 4 days. Mice were imaged to document engraftment of leukemia and then treated with vehicle, 10 mg/kg of DOX, and/or OTX015 as indicated for 2 weeks. Mice were imaged with a Xenogen camera, and total photon counts were recorded. *Indicates total flux (photons/second) that were significantly less in the RUNX1 shRNA and RUNX1 shRNA + OTX015-treated mice compared with the vehicle-treated mice (**P < .01). (G) Kaplan-Meier survival plot of the in vivo activity of DOX and/or OTX015 against Mono-Mac-1/GFP-Luc-i-sh-RUNX1 xenografts in NSG mice. Significance between vehicle and DOX and/or OTX015 was determined by using a Mantel-Cox rank sum test.

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