Jak2^V617F/+-Trp53^−/− and Jak2^V617F/+-Trp53^R172H/– induce a highly penetrant pure erythroid leukemia. (A) Kaplan-Meier comparative survival analysis of reconstituted mice. Cumulative survival was plotted against days after transplantation. P value was determined by the log-rank test. WT control (WT; n = 7); Jak2^V617F/+ (J^VF; n = 7); Jak2^V617F/+Trp53^+/− (J^VFP^+/−; n = 6); Jak2^V617F/+Trp53^−/− (J^VFP^−/−; n = 8); Jak2^V617F/+Trp53^R172H/+ (J^VFP^172/+; n = 6); Jak2^V617F/+Trp53^R172H/– (J^VFP^172/–; n = 8). J^VFP^−/− vs J^VF, P = .0445; J^VFP^−/− vs J^VFP^+/−, P = .0037; J^VFP^172/– vs J^VF, P = .0001; J^VFP^172/– vs J^VFP^172/+, P = .0016. (B) Complete blood count analysis of PB samples and spleen (SPL) weight collected from moribund PEL J^VFP^−/− (n = 8), PEL J^VFP^172/– (n = 8), J^VFP^+/− (n = 6), J^VFP^172/+ (n = 6), and J^VF (n = 7) mice. J^VFP^−/− vs J^VF: white blood cell (WBC), P < .0001; SPL weight, P < .0001. J^VFP^172/– vs J^VF: WBC, P = .0275; HGB, P = .0172; platelet (PLT), P = .0016; SPL weight, P < .0001. J^VFP^+/− vs J^VF: SPL weight, P = .0244. J^VFP^172/+ vs J^VF: SPL weight, P = .0005. (C) Wright-Giemsa smear of PB, histopathologic hematoxylin and eosin (H&E) sections of BM, SPL, and liver from representative moribund PEL J^VFP^−/−and J^VFP^172/–, J^VFP^+/−, J^VFP^172/+, and J^VF mice. Red arrows indicate blasts, yellow arrows indicate neutrophils, and black arrows indicate hepatocytes. Magnification, 1000× for PB and 400× for BM, SPL, and liver. (D) Proportion of PB cells (top) and SPL cells (bottom) of each lineage and CD45^–Lin^–c-Kit⁺ determined by flow cytometric analysis for moribund mice. Lineage markers include CD3, B220, CD11b, and Gr1. J^VF, n = 7; PEL J^VFP^−/−, n = 8; PEL J^VFP^172/–, n = 8; J^VFP^+/−, n = 6; J^VFP^172/+, n = 6. Proportion of CD45^–Lin^–c-Kit⁺ cells in each murine genotype is compared. PB: J^VFP^−/− vs J^VF, P = .002; J^VFP^172/– vs J^VF, P = .0014. SPL: J^VFP^−/− vs J^VF, P < .0001; J^VFP^172/– vs J^VF, P < .0001; J^VFP^+/− vs J^VF, P = .0021; J^VFP^172/+ vs J^VF, P = .0018. (E) Immunohistochemistry (IHC) of liver (CD45, GATA1, and CD71) from representative PEL J^VFP^−/− and PEL J^VFP^172/– mice. Magnification, 400×. (F) Methylcellulose replating assay comparing replating capability of whole BM cells from J^VF(n = 6), PEL J^VFP^−/− (n = 8), and PEL J^VFP^172/– (n = 8) mice. (G) Kaplan-Meier analysis of serial transplant of 1 × 10⁶ whole SPL cells from PEL J^VFP^−/− and PEL J^VFP^172/– mice. P value was determined by using the log-rank test. First transplant (J^VFP^−/−, n = 8; J^VFP^172/–, n = 8); second transplant (J^VFP^−/−, n = 5; J^VFP^172/–, n = 6); third transplant (J^VFP^−/−, n = 10; J^VFP^172/–, n = 6). J^VFP^−/−: first vs second, P = .0005; second vs third, P = .0005; first vs third, P < .0001. J^VFP^172/–: first vs second, P = .0002; first vs third, P = .0003. (H) Genome-wide copy number profile of a representative PEL arising from primary transplant of BM cells derived from J^VFP^172/– donor mouse. Copy number values are rounded to the nearest integer. (I) Frequency plot analysis of a cohort of PEL developing in a p53-deficient background setting (J^VFP^−/−, n = 3; J^VFP^172/–, n = 5). Red lines trace gains, blue lines trace deletions, and gray shading denotes recurrent deletions on mouse chromosome 6. Data are represented as mean ± standard error of the mean (SEM) unless otherwise indicated. The unpaired t test was used to compare the mean of 2 groups in panels B, D, and F. *P < .05, **P ≤ .01, ***P ≤ .001.