American Society of Hematology

Fig. 7.

$Fig. 7. The phosphotyrosine-binding function of the Abl SH2 domain is required for efficient induction of CML-like disease in mice by p210. / BCR/ABL but not by p190. Kaplan-Meier survival curves for recipients of marrow transduced withBCR/ABL wild-type and the indicated SH2 mutants; the individual mice in each arm are designated by the symbols. Several independent transplantation experiments were carried out for each mutant with similar outcome, and the results combined here. (A) Survival curve for recipients of p190 BCR/ABL wild-type (WT)- and SH2 mutant-transduced marrow (p190 WT = 10, p190 R552L = 6, and p190 ΔSH2 = 5); all mice developed CML-like disease (closed symbols). There was no significant difference in survival between p190 WT and p190 R552L recipients, whereas the increased survival of p190 ΔSH2 recipients relative to WT was of borderline significance (P = .005, Mantel-Cox test). (B) Survival curve for recipients of p210 BCR/ABL WT and SH2 mutant-transduced marrow (p210 WT = 15, p210 R1053K = 20, p210 ΔSH2 = 15). All recipients of p210 WT-transduced marrow developed CML-like disease (closed symbols), whereas recipients of marrow transduced with the p210 R1053K SH2 mutant developed predominantly B-lymphoid leukemia (open symbols). Recipients of p210 ΔSH2-transduced marrow developed CML-like disease, B-lymphoid leukemia, or both malignancies simultaneously (indicated by the mixed symbols). Mice were diagnosed with simultaneous B-lymphoid leukemia and CML-like disease if they exhibited the cardinal clinicopathologic features of each disease (bloody pleural effusion and lymphadenopathy for B-lymphoid leukemia; peripheral blood neutrophil count more than 50 × 103/μL, splenomegaly more than 0.5 gm, and pulmonary parenchymal hemorrhage for CML-like disease) to an extent that both malignancies contributed to premorbidity or death. The survival of mice receiving marrow transduced with either p210 SH2 mutant was significantly longer than that of recipients of p210 wild-type-transduced marrow (P < .0001, Mantel-Cox test). (C) Survival curve for recipients of p210 R1053K-transduced marrow that was depleted of B220-expressing cells before transplantation. The survival curves for recipients of p210 R1053K-transduced unfractionated marrow and for p210 WT-transduced marrow (identical to those in panel B) are reproduced for comparison.$

The phosphotyrosine-binding function of the Abl SH2 domain is required for efficient induction of CML-like disease in mice by p210

BCR/ABL but not by p190. Kaplan-Meier survival curves for recipients of marrow transduced withBCR/ABL wild-type and the indicated SH2 mutants; the individual mice in each arm are designated by the symbols. Several independent transplantation experiments were carried out for each mutant with similar outcome, and the results combined here. (A) Survival curve for recipients of p190 BCR/ABL wild-type (WT)- and SH2 mutant-transduced marrow (p190 WT = 10, p190 R552L = 6, and p190 ΔSH2 = 5); all mice developed CML-like disease (closed symbols). There was no significant difference in survival between p190 WT and p190 R552L recipients, whereas the increased survival of p190 ΔSH2 recipients relative to WT was of borderline significance (P = .005, Mantel-Cox test). (B) Survival curve for recipients of p210 BCR/ABL WT and SH2 mutant-transduced marrow (p210 WT = 15, p210 R1053K = 20, p210 ΔSH2 = 15). All recipients of p210 WT-transduced marrow developed CML-like disease (closed symbols), whereas recipients of marrow transduced with the p210 R1053K SH2 mutant developed predominantly B-lymphoid leukemia (open symbols). Recipients of p210 ΔSH2-transduced marrow developed CML-like disease, B-lymphoid leukemia, or both malignancies simultaneously (indicated by the mixed symbols). Mice were diagnosed with simultaneous B-lymphoid leukemia and CML-like disease if they exhibited the cardinal clinicopathologic features of each disease (bloody pleural effusion and lymphadenopathy for B-lymphoid leukemia; peripheral blood neutrophil count more than 50 × 10³/μL, splenomegaly more than 0.5 gm, and pulmonary parenchymal hemorrhage for CML-like disease) to an extent that both malignancies contributed to premorbidity or death. The survival of mice receiving marrow transduced with either p210 SH2 mutant was significantly longer than that of recipients of p210 wild-type-transduced marrow (P < .0001, Mantel-Cox test). (C) Survival curve for recipients of p210 R1053K-transduced marrow that was depleted of B220-expressing cells before transplantation. The survival curves for recipients of p210 R1053K-transduced unfractionated marrow and for p210 WT-transduced marrow (identical to those in panel B) are reproduced for comparison.

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