Macroscopic analysis of ALK-expressing double-transgenic mice. (A) Schematic representation of the generation of double-transgenic mice conditional for the expression of the ALK oncogene in the lymphoid lineage. Three heterozygous transgenic founder mice (pBIL-NA-1, pBIL-NA-2, and pBIL-TA-2) were crossed with homozygous EμSRα tTA mice. Double-transgenic mice were designated as tTA/pBIL-NA-1, tTA/pBIL-NA-2, and tTA/pBIL-TA-2. According to the absence (ON) or presence (OFF) of Dox, the tTA transactivator allows or not the expression of both ALK oncogene and luciferase genes. (B) The size of representative 4-week-old tTA/pBIL-TA-2 (TPM3-ALK) and tTA/pBIL-NA (NPM-ALK) double-transgenic mice are shown in comparison with a control age- and sex-matched tTA littermate animal. Spleen and lymph node enlargements in tTA/pBIL-TA-2 and tTA/pBIL-NA double-transgenic versus control tTA littermate mice are also shown. (C) Necropsy findings in tTA/pBIL-TA-2 and tTA/pBIL-NA double-transgenic mice show (arrows) disseminated lymphadenopathies (LN indicates lymph node) and spleen enlargement associated with multiple skin lesions and hypertrophy of the snout and paws (Cut Nodule indicates cutaneous nodules) in comparison with a control age- and sex-matched tTA littermate animal. (D) Survival curves showing the reduced life time of tTA/pBIL-TA-2 (TA ON) and tTA/pBIL-NA (NA ON) double-transgenic mice compared with control tTA littermate mice and Dox-treated tTA/pBIL-TA-2 (TA OFF) and tTA/pBIL-NA (NA OFF) double-transgenic mice.