SUMOylation controls the rapid transcriptional reprogramming induced by anthracyclines in Acute Myeloid Leukemias

Abstract

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.

SUMOylation inhibitor TAK-981 (subasumstat) synergizes with 5-azacitidine in preclinical models of acute myeloid leukemia

“…Of note, we have recently shown that inhibition of SUMOylation limits the transcriptional reprogramming induced by DNR in AML cells after few hours of treatment. 50 This suggests that inhibitors of SUMOylation could have different global impacts on gene expression depending on the duration of the treatment (hours vs. days) and/or the drugs they are associated with. We also do not exclude that other mechanisms than transcriptional reprogramming might be at play to explain the synergy between AZA and TAK-981.…”

The SUMOylation inhibitor TAK-981 (Subasumstat) triggers IFN-I-dependent activation of Natural Killer cells against Acute Myeloid Leukemias

“…SUMOylation is a post-translational modification, which consists in the covalent conjugation of SUMO-1, -2 or -3 on lysines of thousands of proteins to control their function and fate. One major role of SUMOylation is the control of gene expression through the modification of various transcription factors and co-regulators (6, 7). We and others have recently shown that TAK-981, a first-in-class inhibitor of the SUMO E1 activating enzyme, has potent anti-leukemic activity in AML preclinical models (8).…”