Figure 5.
JNJ-75276617 alters menin-KMT2A target gene expression and prolongs survival of mice bearing NPM1c and KMT2A-r xenografts. (A) Plasma concentrations following a single oral administration of 5 mg/kg (gray squares) or 50 mg/kg (black squares) in mice. The dashed black line represents the IC50 from the in vitro MEIS1 expression assay (45 ± 6 nM, supplemental Figure 3B). (B) Mice bearing subcutaneous (SC) KMT2A-r MOLM-14 xenografts were treated with JNJ-75276617 at the dose levels indicated for 5 weeks. Line underneath the x axis indicates the dosing period. Data are displayed while at least two-thirds of animals remained in the group (n = 9-10/group). ∗ denotes significant tumor regression (P ≤ .05) from initial tumor volume after JNJ-75276617 treatment. (C) Mice bearing SC MOLM-14 xenografts were treated with JNJ-75276617 at the dose levels indicated for 3 or 11 days (n = 2-5/group). Tumors were harvested 16 hours after the last dose, and MEIS1 mRNA levels were assessed. Expression values are calculated relative to tumors treated with vehicle. Bar graphs represent the mean ± standard deviation (SD). ∗P < .0001. (D-G) Mice engrafted with patient-derived AML xenografts harboring KMT2A-r mutation: CBAM-68552 (D,E) or NPM1c: LEXFAM-2734 (F) or AM7577 (G) were treated with JNJ-75276617 at the dose levels indicated. (E) Bone marrows from CBAM-68552–engrafted mice following 4 weeks of drug treatment were analyzed for differentiation markers (human CD11b, CD13, and CD14) by flow cytometry (n = 3). (H,I) Mice engrafted with B-ALL xenografts with KMT2A-r (CBAB-62871; n = 7/group) were treated with JNJ-75276617 for 6 weeks. (I) Bone marrows from CBAB-62871-engrafted mice following 3 weeks of drug treatment were analyzed for differentiation markers (human CD11b, CD13, and CD14) by flow cytometry (n = 3). Individual values are shown as a dot plot, whereas bar graphs represent the mean ± SD. (D,F,G,H) Line underneath the x axis indicates the dosing period. ∗ denotes significant difference (P ≤ .05) in survival between treatment with JNJ-75276617 and vehicle control (n = 7-10/group). (E,I) ∗ denotes a significant difference vs vehicle control (P < .05).

JNJ-75276617 alters menin-KMT2A target gene expression and prolongs survival of mice bearing NPM1c and KMT2A-r xenografts. (A) Plasma concentrations following a single oral administration of 5 mg/kg (gray squares) or 50 mg/kg (black squares) in mice. The dashed black line represents the IC50 from the in vitro MEIS1 expression assay (45 ± 6 nM, supplemental Figure 3B). (B) Mice bearing subcutaneous (SC) KMT2A-r MOLM-14 xenografts were treated with JNJ-75276617 at the dose levels indicated for 5 weeks. Line underneath the x axis indicates the dosing period. Data are displayed while at least two-thirds of animals remained in the group (n = 9-10/group). ∗ denotes significant tumor regression (P ≤ .05) from initial tumor volume after JNJ-75276617 treatment. (C) Mice bearing SC MOLM-14 xenografts were treated with JNJ-75276617 at the dose levels indicated for 3 or 11 days (n = 2-5/group). Tumors were harvested 16 hours after the last dose, and MEIS1 mRNA levels were assessed. Expression values are calculated relative to tumors treated with vehicle. Bar graphs represent the mean ± standard deviation (SD). ∗P < .0001. (D-G) Mice engrafted with patient-derived AML xenografts harboring KMT2A-r mutation: CBAM-68552 (D,E) or NPM1c: LEXFAM-2734 (F) or AM7577 (G) were treated with JNJ-75276617 at the dose levels indicated. (E) Bone marrows from CBAM-68552–engrafted mice following 4 weeks of drug treatment were analyzed for differentiation markers (human CD11b, CD13, and CD14) by flow cytometry (n = 3). (H,I) Mice engrafted with B-ALL xenografts with KMT2A-r (CBAB-62871; n = 7/group) were treated with JNJ-75276617 for 6 weeks. (I) Bone marrows from CBAB-62871-engrafted mice following 3 weeks of drug treatment were analyzed for differentiation markers (human CD11b, CD13, and CD14) by flow cytometry (n = 3). Individual values are shown as a dot plot, whereas bar graphs represent the mean ± SD. (D,F,G,H) Line underneath the x axis indicates the dosing period. ∗ denotes significant difference (P ≤ .05) in survival between treatment with JNJ-75276617 and vehicle control (n = 7-10/group). (E,I) ∗ denotes a significant difference vs vehicle control (P < .05).

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