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bioRxiv · 10.1101/254946

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

Baik, H.·Boulanger, M.·Hosseini, M.·Kowalczyk, J.·Zaghdoudi, S.·Salem, T.·Sarry, J.-E.·Hicheri, Y.·Cartron, G.·Piechaczyk, M.·bossis, g.
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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.

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Baik, H., Boulanger, M., Hosseini, M., Kowalczyk, J., Zaghdoudi, S., Salem, T., Sarry, J.-E., Hicheri, Y., Cartron, G., Piechaczyk, M., bossis, g.. 2018-01-29. Targeting the SUMO pathway primes all-trans-retinoic acid-induced differentiation of non promyelocytic Acute Myeloid Leukemias. https://doi.org/10.1101/254946

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