Epigenetic approach to ALL combinational therapies.

T-ALL is a complex cancer in which multiple lesions accumulate in the genome of hematopoietic progenitors. One frequent alteration is the activation of JAK/STAT pathway, leading to increased cell proliferation and survival. These alterations also affect epigenetic regulators, altering the epigenetic landscape of leukemic cells and further contributing to cancer development. Although current therapy has increased T-ALL prognosis, it is highly toxic and overall survival rates are still far from 100%. This prompts the need to reduce T-ALL therapy-related side effects and develop more efficient targeted therapies. In this context, epigenetics gain importance as an additional therapeutic weapon against JAK/STAT pathway activation. Here, we aim to gain further insights into the epigenetic modifications that cooperate with JAK3 mutations in leukemogenesis. This will lead us to point out candidate targets for epigenetic drugs in combination with current chemotherapy/targeted treatments. In parallel, we will perform a medium-throughput analysis of a wide set of epigenetic compounds in order to find a set of drugs impairing ALL development. The present project will lead us to define effective combination therapies directed against specific sets of cooperating mutations and epigenetic signatures in T-ALL. These combinations would constitute a potentially effective therapy able to reduce current drug doses and toxicity, while increasing their anti-leukemic impact and specificity.