![Figure 4. Severity and penetrance of TEL-PDGFRB–induced myeloproliferation are reduced in the absence of Stat5b. (A) Kaplan-Meier plot shows survival of recipient mice when TEL-PDGFRB is expressed in bone marrow cells harboring targeted deletion of Stat5b (TPiGFP→Stat5b−/−, squares) or wild-type control bone marrow cells (TPiGFP→Stat5b+/+, ○). TPiGFP→Stat5b+/+ mice developed severe MPD (spleen weight median, 890 ± 274 mg; range, 670-1460 mg [n = 6]; WBC median, 139 ± 87 × 109/L [139 000 ± 87 000/μL]; range, 13-237 × 109/L [13 000-237 000/μL] [n = 6]; median survival ± standard error, 33 ± 2.9 days). Severe MPD was detected in 5 of 7 TPiGFP→Stat5b−/− mice at time of death due to disease (spleen weight median, 1220 ± 401 mg; range, 420-1440 mg [n = 7]; WBC median, 103 ±151 × 109/L [103 000 ± 151 000/μL]; range, 6-446 × 109/L [6000-446 000/μL] [n = 7]; median survival ± standard error, 57 ± 60.2 days). Experiment was performed twice, once in the original outbred strain with wild-type littermate control and again with the targeted Stat5b allele backcrossed to balb/c resulting in similar disease latency and severity. Black shapes indicate death due to severe MPD marked by leukocytosis and splenomegaly (WBC, > 50 × 109/L [50 000/μL] and spleen weight, > 450 mg) at time of death due to disease. Shaded shapes represent moderate MPD (WBC, > 15 × 109/L [15 000/μL] and/or spleen weight, > 450 mg) at time of death due to disease. Open shapes indicate animal found dead. GFP was detected in bone marrow, spleen, and peripheral blood of TPiGFP→Stat5b−/− (37% ± 4% [n = 7]; 50% ± 15% [n = 7]; and 58% ± 32% [n = 7], respectively) and TPiGFP→Stat5b+/+ (44% [n = 1]; 50% ± 15% [n = 3]; and 58% ± 32% [n = 3], respectively) recipient mice (data not shown). (B) Flow cytometric detection of mature myeloid (Gr-1+Mac-1+) cells in the spleens of both TPiGFP→Stat5b+/+ and TPiGFP→Stat5b−/− mice 33 days after transplantation. (C) Microscopic images of representative mice at time of death (GFP→Stat5b+/+, 151 days after transplantation; TPiGFP→Stat5b+/+, 29 days after transplantation; and TPiGFP→Stat5b−/−, 29 days after transplantation). Panels show Wright-Giemsa–stained smears of peripheral blood (Ci-iii; 100×), and H&E–stained histologic sections of spleen (Civ-vi; 20×) and liver (Cvii-ix; 40×). These illustrate a normal morphology of peripheral blood, spleen, and liver in the GFP→Stat5b+/+ group, whereas both TPiGFP→Stat5b+/+ and TPiGFP→Stat5b−/− show marked leukocytosis of maturing neutrophils in the peripheral blood, pronounced red pulp expansion by myeloid hyperplasia composed of predominantly maturing forms in the spleen, and sinusoidal and perivascular infiltrates of maturing granulocytic cells in the liver. Arrows indicate clusters of maturing myeloid cells in the liver. (TPiGFP indicates TEL-PDGFRB ires eGFP; MPD, myeloproliferative disease; WBC, peripheral white blood cell count; PB, peripheral blood; Sp, spleen; and Li, liver.)](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/109/9/10.1182_blood-2006-07-036335/4/zh80090700460004.jpeg?Expires=1724259499&Signature=Ej5gyCaRf8MTWS247G0rzfpy34fI14zZH9430tLPXRTQxlcFz2KvLxtT-hFvolzRpVgU1PtDndySv7uaJd8cIe1XoPhdzLamMAssxWW1~uiCAYZoAdbygKCVmgddt4A5rENwZxC76hqZ5mdEXRm9tela6iTPBVSOEXemRh6K0ZtdL5ODFlOTml4zM~dUVAq6zNgQ2vU~xcZEmrYL3ailIQ2whsVB799p-AQFdNeaRivBQkJfGLvZ1~SjKnQGLh9~egWTLi0m4gJUCXYLurztZtTPFiT4R0h1nd2hZty6U8XGIXRYdUZoGB0Gu5YvadN8Et-dXzDTxAv5ww4-zEFFkQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Severity and penetrance of TEL-PDGFRB–induced myeloproliferation are reduced in the absence of Stat5b. (A) Kaplan-Meier plot shows survival of recipient mice when TEL-PDGFRB is expressed in bone marrow cells harboring targeted deletion of Stat5b (TPiGFP→Stat5b−/−, squares) or wild-type control bone marrow cells (TPiGFP→Stat5b+/+, ○). TPiGFP→Stat5b+/+ mice developed severe MPD (spleen weight median, 890 ± 274 mg; range, 670-1460 mg [n = 6]; WBC median, 139 ± 87 × 109/L [139 000 ± 87 000/μL]; range, 13-237 × 109/L [13 000-237 000/μL] [n = 6]; median survival ± standard error, 33 ± 2.9 days). Severe MPD was detected in 5 of 7 TPiGFP→Stat5b−/− mice at time of death due to disease (spleen weight median, 1220 ± 401 mg; range, 420-1440 mg [n = 7]; WBC median, 103 ±151 × 109/L [103 000 ± 151 000/μL]; range, 6-446 × 109/L [6000-446 000/μL] [n = 7]; median survival ± standard error, 57 ± 60.2 days). Experiment was performed twice, once in the original outbred strain with wild-type littermate control and again with the targeted Stat5b allele backcrossed to balb/c resulting in similar disease latency and severity. Black shapes indicate death due to severe MPD marked by leukocytosis and splenomegaly (WBC, > 50 × 109/L [50 000/μL] and spleen weight, > 450 mg) at time of death due to disease. Shaded shapes represent moderate MPD (WBC, > 15 × 109/L [15 000/μL] and/or spleen weight, > 450 mg) at time of death due to disease. Open shapes indicate animal found dead. GFP was detected in bone marrow, spleen, and peripheral blood of TPiGFP→Stat5b−/− (37% ± 4% [n = 7]; 50% ± 15% [n = 7]; and 58% ± 32% [n = 7], respectively) and TPiGFP→Stat5b+/+ (44% [n = 1]; 50% ± 15% [n = 3]; and 58% ± 32% [n = 3], respectively) recipient mice (data not shown). (B) Flow cytometric detection of mature myeloid (Gr-1+Mac-1+) cells in the spleens of both TPiGFP→Stat5b+/+ and TPiGFP→Stat5b−/− mice 33 days after transplantation. (C) Microscopic images of representative mice at time of death (GFP→Stat5b+/+, 151 days after transplantation; TPiGFP→Stat5b+/+, 29 days after transplantation; and TPiGFP→Stat5b−/−, 29 days after transplantation). Panels show Wright-Giemsa–stained smears of peripheral blood (Ci-iii; 100×), and H&E–stained histologic sections of spleen (Civ-vi; 20×) and liver (Cvii-ix; 40×). These illustrate a normal morphology of peripheral blood, spleen, and liver in the GFP→Stat5b+/+ group, whereas both TPiGFP→Stat5b+/+ and TPiGFP→Stat5b−/− show marked leukocytosis of maturing neutrophils in the peripheral blood, pronounced red pulp expansion by myeloid hyperplasia composed of predominantly maturing forms in the spleen, and sinusoidal and perivascular infiltrates of maturing granulocytic cells in the liver. Arrows indicate clusters of maturing myeloid cells in the liver. (TPiGFP indicates TEL-PDGFRB ires eGFP; MPD, myeloproliferative disease; WBC, peripheral white blood cell count; PB, peripheral blood; Sp, spleen; and Li, liver.)
