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The Ubiquitin Family in Hematologic Malignancies

Guillaume Bossis

Research projects

The peptidic post-translational modifiers of the Ubiquitin Family (UbL) are reversibly conjugated to thousands of cellular proteins, the activity, function and/or fate of which they modify. In this way, they play a role as important as that of phosphorylation in virtually all cellular processes. In particular, they are essential for the control of gene expression and is disrupted in a variety of disease situations.

In this context, we are studying how UbL, in particular SUMO, notably through their ability to regulate gene expression programs, are involved in the response of Acute Myeloid Leukemia (AML) to therapies, as AML is a hematological malignancy with a poor prognosis whose treatment has not changed significantly in 40 years.

First, we showed that, in chemosensitive AML, the chemotherapeutic drugs (anthracyclines such as daunorubicin or idarubicin and nucleoside analogues such as aracytin) used in standard treatments induce rapid transcriptional reprogramming, reinforcing the pro-apoptotic effects of the DNA damages they induce. This reprogramming is preceded by a progressive and massive deSUMOylation of cellular proteins due to the ROS (Reactive Oxigen Species)- dependent inactivation of the SUMO activation enzyme E1 and -conjugation enzyme E2 (Bossis et al., 2014). This deSUMOylation is particularly rapid and important on chromatin, especially at the level of promoters and enhancers where SUMOylated proteins are highly enriched, which limits the activation of pro-proliferative and anti-apoptotic genes and facilitates cell death (Boulanger et al., in preparation). On the other hand, in chemoresistant AMLs, anthracyclines neither induce ROS production nor deSUMOylation. However, inhibition of SUMOylation by pharmacological or genetic pathways restores the ROS/SUMO axis, facilitating apoptosis of chemoresistant AMLs (Bossis et al., 2014), pointing to the possibility of a novel therapeutical approach of this deadly disease. More recently, we have shown that deregulation of SUMOylation and ubiquitylation enzyme activity is associated with AML resistance to standard chemotherapies (Gâtel et al., 2020) and might serve as a biomarker of AML response to these treatments (patent EP19305688, 2019).

We have also been interested in the role of SUMOylation in the response of AML to retinoic acid (ATRA)-based differentiation therapies. Such therapies are based on the idea that the restoration of differentiation of leukemic blasts is associated with proliferation arrest followed by cell death due to the naturally limited lifespan of differentiated myeloid cells. Differentiation therapies combining ATRA and arsenic trioxide (As2O3) are highly effective on a minor subtype of AMLs, Acute Promyelocytic Leukemia (APL; 7-10% of AMLs). However, their efficacy is very limited in the other subtypes. We have shown that inhibition of SUMOylation facilitates ATRA-induced differentiation and proliferation arrest in non-APL AMLs by activating specific genes involved in these processes (Baik et al., 2018), paving the way to another novel therapeutical approach of non-APL AMLs.

Thus, our work suggests that targeting SUMOylation might consitute a new therapeutic approach in AMsL, particularly to overcome resistance to the therapies used to treat them so far. The objectives of our current work are: (i) to better understand, at the molecular level, the role of SUMOylation in the response of AMLs to therapies (chemotherapies, differentiation therapies and epidrug-based therapies) and (ii) to validate, in preclinical models of AMLs, the efficacy of SUMOylation targeting in the treatment of AMLs, alone or in combination with existing therapies. This work is carried out in close collaboration with the Department of Clinical Hematology of the University Hospital of Montpellier. Finally, we also aim at developing new tools and molecules to target SUMOylation in AML and more generally cancer

 

Members

Team leader

Mehuli CHAKRABORTY

Stagiaire

+33 (0)4 34 35 9

126

Dana AKL

Doctorant

+33 (0)4 34 35 96 71

Mays AQROUQ

Doctorant

+33 (0)4 34 35 96 70

216

Giovanni BUONOCORE

Doctorant

+33 (0)4 34 35 96 64

219

Guillaume BOSSIS

Chercheur DR2

(+33) 04 34 35 96 64

219

Aude CARUSI

IE-Recherche

+33 (0)4 34 35 96 64

219

Olivier COUX

Chercheur DR2

+33 (0)4 34 35 95 42

312

Chloé DELABY

Stagiaire

+33 (0)4 34 35 96 64

219

Marion DETOLEDO

Chercheur

(+33) 04 34 35 96 75

RDC04

Ludovic GABELLIER

Medecin

+33 (0)4 34 35 96 75

201

Rawan HALLAL

Doctorant

+33 (0)4 34 35 96 70

216

Thibault HOULES

Post-Doc

+33 (0)4 34 35 96 64

219

Marc PIECHACZYK

Chercheur DR1

(+33) 04 34 35 96 68

216 - 201

Yufei QIU

Stagiaire

+33 (0)4 34 35 96 64

219

Denis TEMPE

Chercheur

+33 (0)4 34 35 96 71

216

Selected Publications

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Patents
  • Prognosis method of Leukemia, WO2020/239947
  • Method for identifying ubiquitin and ubiquitin-like enzyme activities WO2020/239949

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Team Overview
Model organism studied
Acute Myeloid Leukemias (cell lines, patient samples, mouse models)
Biological process
Gene regulation, epigenetics, pre-clinical studies, cancer immunotherapies
Biological techniques
Biochemistry, in vivo models, genomic and transcriptomic approaches