Figure 4.
MDS/MPN–like disease in 9p21s+/− mice is driven by the BM microenvironment. (A) Schematic representation of reciprocal transplantation experiment approach. The CD45.1 congenic WT mice BM cells were transplanted to lethal irradiated WT mice (CD45.2) and 9p21+/− mice (CD45.2). (B) Kaplan-Meier plots of WT mice (WT to WT mice, n = 10) and 9p21+/− tumor mice (WT to 9p21+/− mice, n = 9). (C) May-Grünwald-Giemsa staining of peripheral blood smear from a representative sick 9p21+/− mouse. The orange arrow indicates abnormal neutrophil; the red arrow indicates immature myeloid cell; the black arrow indicates immature erythroid cells; and black stars indicate large red blood cells. (D) Complete blood count analysis of mice that had received transplantation with CD45.1 congenic WT mice BM cells. Symbols represent individual mice (WT to WT mice, n = 5; WT to 9p21+/− tumor mice, n = 5). (E) Schematic representation of 9p21+/− BM cells (2- and 6-month-old mice) and WT BM cells (2-month-old mice) transplantation experiment approach. (F) Complete blood count analysis of WT (CD45.2) donor– and 9p21+/− (CD45.2) donor–derived CD45.1 congenic mice peripheral blood at different time points. Symbols represent individual mice (WT to WT mice, n = 6; 2-month-old 9p21+/− to WT mice, n = 5; and 6-month-old 9p21+/− to WT mice, n = 6). (G) The frequency of B cells was analyzed via flow cytometry in 9p21+/− BM cells and WT BM cells transplantation recipient peripheral blood. Symbols represent individual mice (WT to WT mice, n = 6; 2-month-old 9p21+/− to WT mice, n = 5; and 6-month-old 9p21+/− to WT mice, n = 6). (H) Kaplan-Meier plots of Cx3Cr1CreER (n = 7) and Cx3Cr1CreER9p21fl/fl mice (n = 7). (I) Trichrome Masson and reticulin staining of Cx3Cr1CreER9p21fl/fl mice BM. (J) Quantification of the spleen and liver weights. Symbols represent individual mice (WT mice, n = 22; 9p21+/− tumor mice, n = 38; and Cx3Cr1CreER9p21fl/fl tumor mice, n = 7). (K) Complete blood count analysis of mice. Symbols represent individual mice (9p21+/− tumor mice, n = 15; WT mice, n = 17; and Cx3Cr1CreER9p21fl/fl tumor mice, n = 5). Data represent the mean ± SD. Statistical significance was defined using Mann-Whitney test and is shown as follows: ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001 in panels D,F-G,J-K.

MDS/MPN–like disease in 9p21s+/− mice is driven by the BM microenvironment. (A) Schematic representation of reciprocal transplantation experiment approach. The CD45.1 congenic WT mice BM cells were transplanted to lethal irradiated WT mice (CD45.2) and 9p21+/− mice (CD45.2). (B) Kaplan-Meier plots of WT mice (WT to WT mice, n = 10) and 9p21+/− tumor mice (WT to 9p21+/− mice, n = 9). (C) May-Grünwald-Giemsa staining of peripheral blood smear from a representative sick 9p21+/− mouse. The orange arrow indicates abnormal neutrophil; the red arrow indicates immature myeloid cell; the black arrow indicates immature erythroid cells; and black stars indicate large red blood cells. (D) Complete blood count analysis of mice that had received transplantation with CD45.1 congenic WT mice BM cells. Symbols represent individual mice (WT to WT mice, n = 5; WT to 9p21+/− tumor mice, n = 5). (E) Schematic representation of 9p21+/− BM cells (2- and 6-month-old mice) and WT BM cells (2-month-old mice) transplantation experiment approach. (F) Complete blood count analysis of WT (CD45.2) donor– and 9p21+/− (CD45.2) donor–derived CD45.1 congenic mice peripheral blood at different time points. Symbols represent individual mice (WT to WT mice, n = 6; 2-month-old 9p21+/− to WT mice, n = 5; and 6-month-old 9p21+/− to WT mice, n = 6). (G) The frequency of B cells was analyzed via flow cytometry in 9p21+/− BM cells and WT BM cells transplantation recipient peripheral blood. Symbols represent individual mice (WT to WT mice, n = 6; 2-month-old 9p21+/− to WT mice, n = 5; and 6-month-old 9p21+/− to WT mice, n = 6). (H) Kaplan-Meier plots of Cx3Cr1CreER (n = 7) and Cx3Cr1CreER9p21fl/fl mice (n = 7). (I) Trichrome Masson and reticulin staining of Cx3Cr1CreER9p21fl/fl mice BM. (J) Quantification of the spleen and liver weights. Symbols represent individual mice (WT mice, n = 22; 9p21+/− tumor mice, n = 38; and Cx3Cr1CreER9p21fl/fl tumor mice, n = 7). (K) Complete blood count analysis of mice. Symbols represent individual mice (9p21+/− tumor mice, n = 15; WT mice, n = 17; and Cx3Cr1CreER9p21fl/fl tumor mice, n = 5). Data represent the mean ± SD. Statistical significance was defined using Mann-Whitney test and is shown as follows: ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001 in panels D,F-G,J-K.

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