Mice transplanted with K-Ras^G12D–expressing bone marrow cells develop an aggressive T-cell disease. (A) Schematic illustration of the bone marrow transplantation strategy. (B) Kaplan-Meier survival plot of mice transplanted with BM cells derived from K-Ras^G12D/+Mx1-Cre⁺ (KM) and K-Ras^G12D/+ (K) together with 2 × 10⁵ helper cells or with 10⁶ cells derived from the thymi of 2 different diseased animals (donors 9988 and 9980; n = 5 each). Cumulative survival was plotted against days after BMT. KM 5:1 (n = 17) and KM 1:1 (n = 22) developed an aggressive T-cell disease with a median survival of 107 and 114 days, respectively. Sixteen of 17 K-mice were healthy during observation; 1 mouse died of a spontaneous thymic lymphoma. (C) Hematologic and pathologic data of diseased mice. KM mice have increased weight of thymus and spleen, elevated weight blood cell counts, and mild thrombocytopenia. (D) Histopathologic sections of BM (first row, original magnification 40×, left, original magnification 100×, right; hematoxylin and eosin), spleen (bottom left, original magnification 40×; hematoxylin and eosin), and liver (bottom right, original magnification 60×; hematoxylin and eosin) from a representative mouse with T-ALL. Diseased mice show infiltration of lymphoblasts in BM and spleen with destruction of normal architecture as well as extramedullary hematopoiesis in liver. (E) Cre-mediated activation of the oncogenic K-Ras allele. PCR for WT and activated (Δ) K-Ras allele demonstrates the presence of the activated K-Ras allele in thymus, bone marrow, and spleen of 3 representative patients with T-ALL. C indicates control DNA from an patient with KM⁺-induced MPD; MW, molecular weight marker.