Oncogenic activation and therapeutic targeting of PIM1 in T-cell acute lymphoblastic lymphoma

T-cell acute lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm that is thought to be related to T-cell acute lymphoblastic leukemia (T-ALL). Although there are some genetic communalities between T-ALL and T-LBL, T-ALL risk group stratification cannot be extrapolated to T-LBL patients, suggesting the two being biologically different entities. Nevertheless, both T-ALL and T-LBL are treated using intensified chemotherapy which is associated with often debilitating toxicities. Further advances in the treatment of these malignancies require the development of effective targeted drugs.

The identification of PIM1 translocations and elevated PIM1 levels in T-LBL suggest an important oncogenic role for this serine/threonine kinase during T-cell transformation in T-LBL. Nevertheless, the exact molecular mechanism by which PIM1 contributes to the pathology of this disease remains unclear. In this project, we hypothesize that PIM1 forms an intrinsic part of the molecular circuitry that is perturbed in the pathogenesis of T-LBL. We strongly believe that PIM1 activation is critically involved in one or more oncogenic transcriptional programs that contribute to the malignant transformation of T-cell progenitor cells. Therefore, we anticipate that PIM1 will represent a vulnerable target for therapeutic intervention with reduced toxicity and minor side effects due to specific targeting of cancer cells.