Figure 6.
CUX1-deficient mice develop t-MNs after alkylator chemotherapy exposure. (A) Cux1mid, Cux1low, and littermate Ren mice were treated continuously with Dox to induce CUX1 knockdown. At 1 month, mice were treated with an alkylating agent, ENU (100 mg/kg). Peripheral blood was monitored on a biweekly basis. (B) Kaplan-Meier plot showing significantly increased myeloid disease incidence for Cux1mid (n = 8) and Cux1low (n = 12) mice treated with ENU compared with Ren mice treated with ENU (n = 12). Results are shown from 2 independent experiments (n = 4-6 mice per replicate). **P < .01, ***P < .001, log-rank test . Median survival is shown. (C) Complete blood count analysis showing decreased RBC counts following ENU treatment in Cux1mid and Cux1low mice compared with Ren. The mean plus or minus SD is shown. A mixed-effects analysis with the Geisser-Greenhouse correction was performed. (D-E) Red blood cell count (RBC) (D) and red cell distribution width (RDW) (E) from complete blood count analysis at autopsy. (F) The spleen weight at autopsy is shown for Ren, Cux1mid, and Cux1low mice. (G) Representative images from Ren, Cux1mid, and Cux1low spleens stained with hematoxylin and eosin (H&E) are shown; original magnification, ×40. (H) Erythroblasts (CD71+ or Ter119+) in the spleen quantified as a percentage of total cells. (I) Representative Ren, Cux1mid, and Cux1low spleens stained for an immature erythroid marker, anti-GATA1. Original magnification, ×40. The mean ± SD and 1-way ANOVA P values are shown. (J) RI-RIV erythroid precursor populations quantified as a percentage of erythroblasts in the spleen. The mean ± SD is shown, and P values were calculated using a 2-way ANOVA. Representative flow plots for the erythroblast markers CD71 and Ter119 are shown. (K) MEPs in the spleen, as a percentage of white blood cells. The mean ± SD and 1-way ANOVA P values are shown. Panels F-K represent mice that develop nonlymphoid disease after ENU for Cux1mid (n = 3) and Cux1low mice (n = 10). *P < .05; **P < .01; ***P < .001; ****P < .0001.

CUX1-deficient mice develop t-MNs after alkylator chemotherapy exposure. (A) Cux1mid, Cux1low, and littermate Ren mice were treated continuously with Dox to induce CUX1 knockdown. At 1 month, mice were treated with an alkylating agent, ENU (100 mg/kg). Peripheral blood was monitored on a biweekly basis. (B) Kaplan-Meier plot showing significantly increased myeloid disease incidence for Cux1mid (n = 8) and Cux1low (n = 12) mice treated with ENU compared with Ren mice treated with ENU (n = 12). Results are shown from 2 independent experiments (n = 4-6 mice per replicate). **P < .01, ***P < .001, log-rank test . Median survival is shown. (C) Complete blood count analysis showing decreased RBC counts following ENU treatment in Cux1mid and Cux1low mice compared with Ren. The mean plus or minus SD is shown. A mixed-effects analysis with the Geisser-Greenhouse correction was performed. (D-E) Red blood cell count (RBC) (D) and red cell distribution width (RDW) (E) from complete blood count analysis at autopsy. (F) The spleen weight at autopsy is shown for Ren, Cux1mid, and Cux1low mice. (G) Representative images from Ren, Cux1mid, and Cux1low spleens stained with hematoxylin and eosin (H&E) are shown; original magnification, ×40. (H) Erythroblasts (CD71+ or Ter119+) in the spleen quantified as a percentage of total cells. (I) Representative Ren, Cux1mid, and Cux1low spleens stained for an immature erythroid marker, anti-GATA1. Original magnification, ×40. The mean ± SD and 1-way ANOVA P values are shown. (J) RI-RIV erythroid precursor populations quantified as a percentage of erythroblasts in the spleen. The mean ± SD is shown, and P values were calculated using a 2-way ANOVA. Representative flow plots for the erythroblast markers CD71 and Ter119 are shown. (K) MEPs in the spleen, as a percentage of white blood cells. The mean ± SD and 1-way ANOVA P values are shown. Panels F-K represent mice that develop nonlymphoid disease after ENU for Cux1mid (n = 3) and Cux1low mice (n = 10). *P < .05; **P < .01; ***P < .001; ****P < .0001.

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