Fig. 5 ALRN-6924 shows robust antileukemic activity in primary AML cells and in vivo. ALRN-6924 shows robust antileukemic activity in primary AML cells.

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Fig. 5 ALRN-6924 shows robust antileukemic activity in primary AML cells and in vivo. ALRN-6924 shows robust antileukemic activity in primary AML cells and in vivo. (A) Dose- and time-dependent effects on cellular proliferation measured by trypan blue exclusion in primary AML cells treated with increasing concentrations of ALRN-6924 (data shown as mean ± SD of technical triplicates). (B) Dose-dependent effects of ALRN-6924 on clonogenic capacity of primary AML cells (n = 4) compared to healthy peripheral blood mononuclear cells (PBMNCs) isolated from cord blood (n = 3) and bone marrow mononuclear cells (BMMNCs) isolated from one AML patient in clinical remission (data shown as mean ± SD; P statistics determined using unpaired two-tailed Student’s t test). (C) FACS analysis of cellular viability (left panel) and apoptosis (right panel, plotted as fold change relative to baseline) measured by annexin V and DAPI staining in leukemia stem cell–enriched (CD34+CD38−) primary bone marrow cells from AML patients (n = 3) and healthy donors (n = 3) 48 hours after treatment with 5 μM ALRN-6924 (data shown as mean ± SD, unpaired one-tailed Student’s t test). (D) Serial replating capacity of AML cell lines treated with either 0.5 μM ALRN-6924 or 0.5 μM RG7388, measured by CFC assay. (E) Human AML cellular engraftment analysis by FACS of mouse bone marrow (BM) from experimental animals 5 weeks after the start of treatment. Human AML cells were identified by costaining mouse BM cells with human CD45 and mouse CD45.1 antibodies [BIW, two times per week (n = 10); TIW, three times per week (n = 5)]. (F) Kaplan-Meier curve showing overall survival of mice xenotransplanted with MOLM13 AML cells and treated with ALRN-6924 or vehicle. (G) Median survival times for the curves shown in (F). (H) FACS analysis of mouse hematopoietic stem and progenitor frequencies after treatment with ALRN-6924 (20 mg/kg) TIW for 4 weeks (HSC = LSK CD150+CD48−, LSK = Lin−Sca+Kit+, and LK = Lin−Kit+ progenitors). (I) Neutrophil and platelet counts assessed by Hemavet analysis of peripheral blood from mice (n = 10) on treatment with ALRN-6924 (20 mg/kg) TIW for 4 weeks. Data shown as the mean ± SD; *P < 0.05, **P < 0.01, ***P < 0.001. Luis A. Carvajal et al., Sci Transl Med 2018;10:eaao3003 Published by AAAS