Figure 2.
Serial transplantation of Asxl1–/–Ezh2–/– cells lead to aggressive CLL. (A) The percentage of B220–/low B cells in CD45.2+ splenocytes from mice that received primary transplant with indicated genotypes and disease phenotypes are shown. Asxl1–/–Ezh2–/– (MDS/MPN, LPD), n = 4; all other sample types, n = 3. (B) The heat map shows normalized read counts of 124 IGHV in the BM from mice that received primary transplant with the indicated genotype. The monoclones with substantial expansion are pointed out. (C) Kaplan-Meier survival curves of secondary transplants; mice were transplanted with BM cells harvested from mice that received primary transplant with the indicated genotypes and disease phenotypes. WT, n = 5; Asxl1–/–, n = 5; Ezh2–/– (MDS/MPN, LPD), n = 10; Asxl1–/–Ezh2–/– (MDS/MPN, LPD), n = 13; Asxl1–/–Ezh2–/– (MDS/MPN), n = 3 mice. Representative images of the SPs are shown. (D) Engraftments of total donor cells (CD45.2+) and the ratios of myeloid and lymphoid populations in the donor population from the BM and SP (as indicated) of WT (BM, n = 4; SP, n = 3) and Asxl1–/–Ezh2–/– dKO secondary CLL (n = 6) mice. (E) May-Grunwald Giesma staining of BM (original magnification x40) cells and PB (x40) smears, and hematoxylin and eosin staining of the SP (x20) and LV (x10) of Asxl1–/–Ezh2-/- dKO secondary CLL mice. (F) Representative flow cytometry profiling of CLL cells in BM from Asxl1–/–Ezh2–/– dKO secondary CLL mice. (G) The dot plot represents the percentages of CD19+CD5+ cells in donor cells from BM (n = 3) and SPs (n = 2) from Asxl1–/–Ezh2–/– dKO secondary CLL mice compared with WT BM (n = 3). (H) Proportions of κ/λ light chains in CD19+ donor splenocytes isolated from Asxl1–/–Ezh2–/– dKO secondary CLL or WT mice as indicated. (I) Kaplan-Meier survival curves of tertiary transplants. Mice were transplanted with BM cells and splenocytes from a secondary Asxl1–/–Ezh2–/– CLL mouse or splenocytes from a secondary TCL1 CLL mouse. Plots show mean ± SEM. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001, unpaired t test. A/E, Asxl1-/-Ezh2-/-; LV, liver; SP, spleen; TCL1, T-cell leukemia/lymphoma 1A oncogene.

Serial transplantation of Asxl1–/–Ezh2–/– cells lead to aggressive CLL. (A) The percentage of B220–/low B cells in CD45.2+ splenocytes from mice that received primary transplant with indicated genotypes and disease phenotypes are shown. Asxl1–/–Ezh2–/– (MDS/MPN, LPD), n = 4; all other sample types, n = 3. (B) The heat map shows normalized read counts of 124 IGHV in the BM from mice that received primary transplant with the indicated genotype. The monoclones with substantial expansion are pointed out. (C) Kaplan-Meier survival curves of secondary transplants; mice were transplanted with BM cells harvested from mice that received primary transplant with the indicated genotypes and disease phenotypes. WT, n = 5; Asxl1–/–, n = 5; Ezh2–/– (MDS/MPN, LPD), n = 10; Asxl1–/–Ezh2–/– (MDS/MPN, LPD), n = 13; Asxl1–/–Ezh2–/– (MDS/MPN), n = 3 mice. Representative images of the SPs are shown. (D) Engraftments of total donor cells (CD45.2+) and the ratios of myeloid and lymphoid populations in the donor population from the BM and SP (as indicated) of WT (BM, n = 4; SP, n = 3) and Asxl1–/–Ezh2–/– dKO secondary CLL (n = 6) mice. (E) May-Grunwald Giesma staining of BM (original magnification x40) cells and PB (x40) smears, and hematoxylin and eosin staining of the SP (x20) and LV (x10) of Asxl1–/–Ezh2-/- dKO secondary CLL mice. (F) Representative flow cytometry profiling of CLL cells in BM from Asxl1–/–Ezh2–/– dKO secondary CLL mice. (G) The dot plot represents the percentages of CD19+CD5+ cells in donor cells from BM (n = 3) and SPs (n = 2) from Asxl1–/–Ezh2–/– dKO secondary CLL mice compared with WT BM (n = 3). (H) Proportions of κ/λ light chains in CD19+ donor splenocytes isolated from Asxl1–/–Ezh2–/– dKO secondary CLL or WT mice as indicated. (I) Kaplan-Meier survival curves of tertiary transplants. Mice were transplanted with BM cells and splenocytes from a secondary Asxl1–/–Ezh2–/– CLL mouse or splenocytes from a secondary TCL1 CLL mouse. Plots show mean ± SEM. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001, unpaired t test. A/E, Asxl1-/-Ezh2-/-; LV, liver; SP, spleen; TCL1, T-cell leukemia/lymphoma 1A oncogene.

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