T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are aggressive hematologic malignancies that require treatment with intensified chemotherapy. PIM1 is a constitutively active kinase that is overexpressed in a large number of cancer subtypes. Several PIM inhibitors are currently tested in clinical trials for the treatment of different malignancies. The identification of a PIM1 translocation in a case of human T-LBL and the notion that PIM1 is overexpressed in a substantial fraction of human T-ALLs and T-LBLs suggests an important oncogenic role for this serine/threonine kinase factor during T-cell transformation. Nevertheless, the exact molecular mechanism by which PIM1 contributes to the pathology of this disease remains unclear, and the role of PIM1 as a therapeutic target for the treatment of these diseases has not been properly evaluated. In this project, we will identify the genetic mechanisms that cause aberrant PIM1 activation, define the oncogenic pathways downstream of PIM1 during T-cell transformation and evaluate PIM1 inhibition as a new therapeutic strategy in human T-cell leukemia and lymphoma. We anticipate that PIM1 will represent a vulnerable target for therapeutic intervention with reduced toxicity an minor side effects due to specific targeting of cancer cells.