Figure 4
Figure 4. Aged Apcmin mice develop MDS/MPD. (A) White cell count (WCC × 103/μL) and spleen weight (mg) from Apcmin mice with MDS/MPD. WCC 19.2 × 103/μL Apcmin versus 7.4 × 103/μL WT, P < .01; neutrophil count 5.7 × 103/μL Apcmin versus 1.6 × 103/μL WT, P < .01; and spleen weight 0.69 g Apcmin versus 0.09 g WT, P < .01. (B) Peripheral blood parameters, including red cell count (RCC × 106/μL), hematocrit (HCT%), mean corpuscular volume (MCV fl), monocyte count (×103/μL), red cell distribution width (RDW%), and platelet count (×103/μL). Red cell count: 2.7 × 106/μL Apcmin versus 9.7 × 106/μL WT, P < .01; HCT: 17.4% Apcmin versus 42.8% WT, P < .01; MCV: 66.5 fl Apcmin versus 45 fl WT P < .01; monocyte count: 1.2 × 103/μL Apcmin versus 0.3 × 103/μL WT, P = .03; RDW: 23.7% Apcmin versus 17.3% WT, P < .01. (C) Hematopoietic stem and progenitor cell numbers expressed as a percentage of total bone marrow. LKS+ (lineagelowcKithighSca-1+ enriched for HSCs), LKS+SLAM (LKS+CD150+CD48− highly enriched for long-term HSC), GMPs, CMPs, and MEPs. (D) Peripheral blood films (magnification ×40) and splenic histology (magnification ×10) demonstrating macrocytic anemia with anisopoikilocytosis in Apcmin mice and effacement of normal splenic architecture by extramedullary hematopoiesis (images taken with Nikon Eclipse E400 microscope and digital camera; SPOT Diagnostic Instruments, model 2.2.1). (E) Colony-formation assays in cytokine-enriched methylcellulose from 104 bone marrow cells and (F) 105 spleen cells. Megakaryocyte colonies (CFU-Mk), megakaryocyte-erythroid colonies (CFU-EMk), mixed multilineage colonies (CFU-GEMM), granulocyte-monocyte colonies (CFU-GM), and blast forming units-erythroid colonies (BFU-E). Bone marrow: 41.5 Apcmin versus 36.8 colonies/104 cells WT, P = .35; BFU-E: 10.2 Apcmin versus 3.3 colonies/104 cells WT, P < .01; spleen: 84.2 Apcmin versus 35.8 colonies/105 cells WT, P < .01; CFU-GM: 58.8 Apcmin versus 30.8 colonies/105 cells WT, P < .01; BFU-E: 13.2 Apcmin versus 1.8 colonies/105 cells WT, P < .01). (G) Erythroid maturation flow cytometric analysis. Ery1 (CD71high, Ter119mid), Ery2 (CD71high, Ter119high), Ery3 (CD71mid, Ter119high), and Ery4 (CD71low, Ter119high). (H) Graphical representation of erythroid maturation demonstrating shift toward immature (Ery1/2) development. 2.5% and 34.8% Apcmin versus 0.2% and 8.0% WT for Ery1 and Ery2, respectively, P < .01; 3.1% and 0.6% Apcmin versus 11.4% and 3.2% WT for Ery3 and Ery4, respectively, P < .01.

Aged Apcmin mice develop MDS/MPD. (A) White cell count (WCC × 103/μL) and spleen weight (mg) from Apcmin mice with MDS/MPD. WCC 19.2 × 103/μL Apcmin versus 7.4 × 103/μL WT, P < .01; neutrophil count 5.7 × 103/μL Apcmin versus 1.6 × 103/μL WT, P < .01; and spleen weight 0.69 g Apcmin versus 0.09 g WT, P < .01. (B) Peripheral blood parameters, including red cell count (RCC × 106/μL), hematocrit (HCT%), mean corpuscular volume (MCV fl), monocyte count (×103/μL), red cell distribution width (RDW%), and platelet count (×103/μL). Red cell count: 2.7 × 106/μL Apcmin versus 9.7 × 106/μL WT, P < .01; HCT: 17.4% Apcmin versus 42.8% WT, P < .01; MCV: 66.5 fl Apcmin versus 45 fl WT P < .01; monocyte count: 1.2 × 103/μL Apcmin versus 0.3 × 103/μL WT, P = .03; RDW: 23.7% Apcmin versus 17.3% WT, P < .01. (C) Hematopoietic stem and progenitor cell numbers expressed as a percentage of total bone marrow. LKS+ (lineagelowcKithighSca-1+ enriched for HSCs), LKS+SLAM (LKS+CD150+CD48− highly enriched for long-term HSC), GMPs, CMPs, and MEPs. (D) Peripheral blood films (magnification ×40) and splenic histology (magnification ×10) demonstrating macrocytic anemia with anisopoikilocytosis in Apcmin mice and effacement of normal splenic architecture by extramedullary hematopoiesis (images taken with Nikon Eclipse E400 microscope and digital camera; SPOT Diagnostic Instruments, model 2.2.1). (E) Colony-formation assays in cytokine-enriched methylcellulose from 104 bone marrow cells and (F) 105 spleen cells. Megakaryocyte colonies (CFU-Mk), megakaryocyte-erythroid colonies (CFU-EMk), mixed multilineage colonies (CFU-GEMM), granulocyte-monocyte colonies (CFU-GM), and blast forming units-erythroid colonies (BFU-E). Bone marrow: 41.5 Apcmin versus 36.8 colonies/104 cells WT, P = .35; BFU-E: 10.2 Apcmin versus 3.3 colonies/104 cells WT, P < .01; spleen: 84.2 Apcmin versus 35.8 colonies/105 cells WT, P < .01; CFU-GM: 58.8 Apcmin versus 30.8 colonies/105 cells WT, P < .01; BFU-E: 13.2 Apcmin versus 1.8 colonies/105 cells WT, P < .01). (G) Erythroid maturation flow cytometric analysis. Ery1 (CD71high, Ter119mid), Ery2 (CD71high, Ter119high), Ery3 (CD71mid, Ter119high), and Ery4 (CD71low, Ter119high). (H) Graphical representation of erythroid maturation demonstrating shift toward immature (Ery1/2) development. 2.5% and 34.8% Apcmin versus 0.2% and 8.0% WT for Ery1 and Ery2, respectively, P < .01; 3.1% and 0.6% Apcmin versus 11.4% and 3.2% WT for Ery3 and Ery4, respectively, P < .01.

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