Targeting the SUMO pathway primes all-trans-retinoic acid-induced differentiation of non promyelocytic Acute Myeloid Leukemias

Abstract

Differentiation therapies using All-trans-retinoic acid (ATRA) are highly efficient at treating Acute Promyelocytic Leukemia (APL), a minor subtype of Acute Myeloid Leukemias (AML). However, their efficacy, if any, is very limited in the case of non-APL AMLs. We report here that the inhibition of SUMOylation, a post-translational modification related to ubiquitinylation, restores the pro-differentiation and anti-proliferative activities of retinoids in non-APL AMLs. Controlled inhibition of SUMOylation with pharmacological inhibitors (2-D08 or anacardic acid), or via overexpression of SENP desumoylases, strongly enhances the ATRA-induced expression of key genes involved in differentiation, proliferation and apoptosis in non-APL AML cells. This activates ATRA-induced terminal myeloid differentiation and reduces cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation by overexpressing the SUMO-conjugating enzyme Ubc9 dampens the expression of ATRA-responsive genes and prevents differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize non-APL AML patients to retinoids and improve the treatment of this poor prognosis cancer, which has not significantly changed over the past 40 years.