Abstract
Differentiation therapies are a promising alternative to genotoxic-based chemotherapies in the treatment of many cancers. In particular, All-trans-retinoic acid (ATRA) is successfully used for Acute Promyelocytic Leukemias, a subtype of Acute Myeloid Leukemias. However, its clinical efficiency is very limited in the other AML subtypes, in particular because of epigenetic repression of ATRA-responsive genes. SUMOs are a family of post-translational modifiers related to ubiquitin and their conjugation, sumoylation, to their substrate proteins regulate many processes including gene transcription. The aim of my thesis was to understand the role of sumoylation in AML responses to treatments. I showed that sumoylation represses ATRA-induced differentiation in many AML cell lines and primary patient samples, including those resistant to chemotherapies. Inhibition of sumoylation with pharmacological inhibitors or overexpression of desumoylases markedly increased their differentiation by ATRA and increasing sumoylation by overexpression of SUMO or its conjugating enzyme Ubc9 strongly reduce ATRA efficiency. Inhibition of sumoylation synergize with ATRA to arrest AML cells proliferation both in vitro and in vivo. Mechanistically, inhibition of sumoylation primes AML cells for differentiation by facilitating the expression of master genes of the myeloid differentiation. Targeting the SUMO pathway thus constitute a promising approach to sensitize AML to differentiation therapies.