TPM3-ALK (Tropomyosin 3-Anaplastic lymphoma kinase) is oncogenic tyrosine kinase implicated in the pathogenesis of human ALK-positive lymphoma. We have developed novel conditional mouse models for ALK-induced lymphomagenesis, by using the tetracycline regulatory system under the control of the EmuSRalpha enhancer/promoter. The expression of oncogene resulted in the arrest of the differentiation of early B-cells and lymphomagenesis associated with skin keratoacanthoma lesions, likely due to aberrant ALK expression in keratinocytes. The inactivation of the ALK oncogene upon doxycycline or the specific ALK inhibitor (PF-2341066)treatment was sufficient to induce sustained regression of both hematopoietic tumors and skin disease, illustrating the value of these mouse models for the validation of ALK tyrosine kinase inhibitors.