Targeting the SUMO Pathway Primes An-trans Retinoic Acid-Induced Differentiation of Nonpromyelocytic Acute Myeloid Leukemias

Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (API.), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-API AML, We report here that inhibition of SUMOylation, a posttranslational modification related to ubiquitination, restores the pro-differentiation and antiproliferative activities of retinoids in non-APL AML. Controlled inhibition of SUMOylation with the pharmacologic inhibitors 2-D08 or anacardic acid, or via overexpression of SENP deSUMOylases, enhanced the ATRA-induced expression of key genes involved in differentiation, proliferation, and apoptosis in non-API AML cells. This activated ATRA-induced terminal myeloid differentiation and reduced cell proliferation and viability, including in AML cells resistant to chemotherapeutic drugs. Conversely, enhancement of SUMOylation via overexpression of the SUMO-conjugating enzyme Ubc9 dampened expression of ATRA-responsive genes and prevented differentiation. Thus, inhibition of the SUMO pathway is a promising strategy to sensitize patients with non-APL AML to retinoids and improve the treatment of this poor-prognosis cancer. Significance: SUMOylation silences key AURA-responsive genes in nonpromyelocytic acute myeloid leukemias. (C) 2018 AACR.