Figure 1.
dKO of Asxl1 and Ezh2 leads to the development of myelodysplastic disorders with high penetrance. (A) Schematic diagram of the primary transplantation experiment. (B) Percentages of LSK, myeloid progenitors (Lin–c-kit+Sca1–), and their subpopulations: LT-HSCs (CD48–CD150+), ST-HSCs (CD48–CD150–), MPP3/4 (CD48+CD150–), MPP2 (CD48+CD150+), GMP (CD16/32+CD34+), CMP (CD16/32–CD34+), and MEP (CD16/32–CD34–) in BM from indicated mutant mice 4 weeks after tamoxifen treatment are shown. WT, n = 6; all other groups, n = 5. (C) Absolute cell counts of CD45.2+ LSK and myeloid progenitors in BM are shown. WT, n = 6; all other groups, n = 5. (D) Kaplan-Meier survival curves of WT (n = 8), Asxl1–/– (n = 6), Ezh2–/– (n = 8), and Asxl1–/–Ezh2–/– (n = 13) mice in primary transplantation. (E) Representative images of May-Grunwald Giemsa staining of BM from indicated mice and PB smears from Asxl1–/–Ezh2–/– mice. Myeloid dysplastic cells such as monolobated megalokaryocytes (1), pseudo–Pelger-Huët anomalies (2), binucleated megakaryocytes (3), Howell Jolly bodies (4), and giant platelets (5) were found in the mice with myelodysplasia. (F) Blood counts of WT, Asxl1–/–, Ezh2–/–, and Asxl1–/–Ezh2–/– mice with indicated disease phenotypes in primary transplantation. Statistical analysis is shown for the indicated groups, unless otherwise stated. (G) The percentages of hematopoietic cells Bl/Pro, My/Met, band cells, and Ne in granulopoiesis from WT and KO mice with MDS/MPN phenotypes. WT and Asxl1–/–, n = 3 each; EZH2–/–, n = 2; Asxl1–/–Ezh2–/–, n = 5. (H) Spleen weights (left) and representative photos of spleens (right) for the indicated genotypes and disease phenotypes. WT, n = 5; Asxl1–/–, n = 6; Ezh2–/–, n = 8; Asxl1–/–Ezh2–/–, n = 12. Plots show mean ± standard error of the mean (SEM). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001, unpaired t test. Bl/Pro, blasts/promyelocytes; CMP, common myeloid progenitor; ET, essential thrombocythemia; GMP, granulocyte-monocyte progenitor; Hgb, hemoglobin; Lin–, lineage negative; LT-HSC, long-term HSC; MEP, megakaryocyte–erythroid progenitor; MPP3/4, multipotent progenitor 3/4; My/Met, myelocytes/metamyelocytes; Ne, neutrophils; Plt, platelets; PV, polycythemia vera; RBC, red blood cells; ST-HSC, short-term HSC; WBC, white blood cells.

dKO of Asxl1 and Ezh2 leads to the development of myelodysplastic disorders with high penetrance. (A) Schematic diagram of the primary transplantation experiment. (B) Percentages of LSK, myeloid progenitors (Lin–c-kit+Sca1–), and their subpopulations: LT-HSCs (CD48–CD150+), ST-HSCs (CD48–CD150–), MPP3/4 (CD48+CD150–), MPP2 (CD48+CD150+), GMP (CD16/32+CD34+), CMP (CD16/32–CD34+), and MEP (CD16/32–CD34–) in BM from indicated mutant mice 4 weeks after tamoxifen treatment are shown. WT, n = 6; all other groups, n = 5. (C) Absolute cell counts of CD45.2+ LSK and myeloid progenitors in BM are shown. WT, n = 6; all other groups, n = 5. (D) Kaplan-Meier survival curves of WT (n = 8), Asxl1–/– (n = 6), Ezh2–/– (n = 8), and Asxl1–/–Ezh2–/– (n = 13) mice in primary transplantation. (E) Representative images of May-Grunwald Giemsa staining of BM from indicated mice and PB smears from Asxl1–/–Ezh2–/– mice. Myeloid dysplastic cells such as monolobated megalokaryocytes (1), pseudo–Pelger-Huët anomalies (2), binucleated megakaryocytes (3), Howell Jolly bodies (4), and giant platelets (5) were found in the mice with myelodysplasia. (F) Blood counts of WT, Asxl1–/–, Ezh2–/–, and Asxl1–/–Ezh2–/– mice with indicated disease phenotypes in primary transplantation. Statistical analysis is shown for the indicated groups, unless otherwise stated. (G) The percentages of hematopoietic cells Bl/Pro, My/Met, band cells, and Ne in granulopoiesis from WT and KO mice with MDS/MPN phenotypes. WT and Asxl1–/–, n = 3 each; EZH2–/–, n = 2; Asxl1–/–Ezh2–/–, n = 5. (H) Spleen weights (left) and representative photos of spleens (right) for the indicated genotypes and disease phenotypes. WT, n = 5; Asxl1–/–, n = 6; Ezh2–/–, n = 8; Asxl1–/–Ezh2–/–, n = 12. Plots show mean ± standard error of the mean (SEM). ∗P < .05; ∗∗P < .01; ∗∗∗P < .001, unpaired t test. Bl/Pro, blasts/promyelocytes; CMP, common myeloid progenitor; ET, essential thrombocythemia; GMP, granulocyte-monocyte progenitor; Hgb, hemoglobin; Lin–, lineage negative; LT-HSC, long-term HSC; MEP, megakaryocyte–erythroid progenitor; MPP3/4, multipotent progenitor 3/4; My/Met, myelocytes/metamyelocytes; Ne, neutrophils; Plt, platelets; PV, polycythemia vera; RBC, red blood cells; ST-HSC, short-term HSC; WBC, white blood cells.

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