Targeting the SUMO Pathway Primes All-trans Retinoic Acid-Induced Differentiation of Nonpromyelocytic Acute Myeloid Leukemias - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2018

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

Résumé

Differentiation therapies using all-trans retinoic acid (ATRA) are highly efficient at treating acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia (AML). However, their efficacy, if any, is limited in the case of non-APL AML. We report here that inhibition of SUMOylation, a posttranslational modification related to ubiquitination, restores the prodifferentiation 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-APL 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 ATRA-responsive genes in nonpromyelocytic acute myeloid leukemias. Cancer Res; 78(10); 2601-13. \textcopyright2018 AACR.
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hal-02348613 , version 1 (05-11-2019)

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Hayeon Baik, Mathias Boulanger, Mohsen Hosseini, Julie Kowalczyk, Sonia Zaghdoudi, et al.. Targeting the SUMO Pathway Primes All-trans Retinoic Acid-Induced Differentiation of Nonpromyelocytic Acute Myeloid Leukemias. Cancer Research, 2018, 78 (10), pp.2601--2613. ⟨10.1158/0008-5472.CAN-17-3361⟩. ⟨hal-02348613⟩
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