Figure 3.
Inhibition of canonical BMP4 signaling reduces ALL CNS infiltration and neurological clinical symptoms. (A) Outline of the in vivo experimental design for panels (B-F). Mice were transplanted with BMP4high primary samples at day 0 (samples from patients #1, #2, and #3, which were shown to engraft in 100% animals in previous experiments, were used). Leukemia development was monitored, and 8 days after injection, mice transplanted with each sample (6-8 animals per sample) were randomly divided into 2 groups (n = 11 mice per group) and treated with DMH1 or control DMSO. All animals were euthanized upon detection of hind limb paralysis in DMSO control mice. (B) Both control DMSO- and DMH1-treated mice (n = 11 mice per group) showed similar engraftment in peripheral organs. Bars show mean percentages (±standard deviation [SD]) of CD19+ leukemic blasts in BM, spleen, and PB. (C) CNS leukemia infiltration was reduced in DMH1- vs control DMSO-treated animals (n = 11 mice per group). Each data point represents a single mouse transplanted with blasts from patients #1, #2, or #3 (shown as circles, squares, or triangles), and lines represent the mean percentage of CD19 leukemic blasts in each group (**P ≤ .01; 2-tailed Mann-Whitney U test). (D) Bars represent average serum IL-6 levels measured in DMSO- and DMH1-treated mice at euthanasia (n = 4 mice per group; *P ≤ .05; 2-tailed Mann-Whitney U test). (E) Olfactory habituation–dishabituation test of healthy (green triangles), DMSO- (blue circles), and DMH1-treated (red squares) mice (n = 4 mice per group). Data represent the exploration time (mean ± SD) of successive cotton swabs soaked in octanal, heptanal, or anisole. Two-way ANOVA followed by Bonferroni correction showed significant differences for heptanal and anisole odors: *P ≤ .05 and **P ≤ .01 show significant differences between vehicle-DMSO and healthy control mice; #P ≤ .05 shows significant differences between DMSO- and DMH1-treated mice. (F) The incidence of hind limb paralysis in DMH1-treated mice was notably reduced with respect to the DMSO control group.

Inhibition of canonical BMP4 signaling reduces ALL CNS infiltration and neurological clinical symptoms. (A) Outline of the in vivo experimental design for panels (B-F). Mice were transplanted with BMP4high primary samples at day 0 (samples from patients #1, #2, and #3, which were shown to engraft in 100% animals in previous experiments, were used). Leukemia development was monitored, and 8 days after injection, mice transplanted with each sample (6-8 animals per sample) were randomly divided into 2 groups (n = 11 mice per group) and treated with DMH1 or control DMSO. All animals were euthanized upon detection of hind limb paralysis in DMSO control mice. (B) Both control DMSO- and DMH1-treated mice (n = 11 mice per group) showed similar engraftment in peripheral organs. Bars show mean percentages (±standard deviation [SD]) of CD19+ leukemic blasts in BM, spleen, and PB. (C) CNS leukemia infiltration was reduced in DMH1- vs control DMSO-treated animals (n = 11 mice per group). Each data point represents a single mouse transplanted with blasts from patients #1, #2, or #3 (shown as circles, squares, or triangles), and lines represent the mean percentage of CD19 leukemic blasts in each group (**P ≤ .01; 2-tailed Mann-Whitney U test). (D) Bars represent average serum IL-6 levels measured in DMSO- and DMH1-treated mice at euthanasia (n = 4 mice per group; *P ≤ .05; 2-tailed Mann-Whitney U test). (E) Olfactory habituation–dishabituation test of healthy (green triangles), DMSO- (blue circles), and DMH1-treated (red squares) mice (n = 4 mice per group). Data represent the exploration time (mean ± SD) of successive cotton swabs soaked in octanal, heptanal, or anisole. Two-way ANOVA followed by Bonferroni correction showed significant differences for heptanal and anisole odors: *P ≤ .05 and **P ≤ .01 show significant differences between vehicle-DMSO and healthy control mice; #P ≤ .05 shows significant differences between DMSO- and DMH1-treated mice. (F) The incidence of hind limb paralysis in DMH1-treated mice was notably reduced with respect to the DMSO control group.

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