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The Ubiquitin Family in Hematologic Malignancies

GUILLAUME BOSSIS / MARC PIECHACZYK

Research projects

 The team conducts two projects in parallel to better understand cancer, in particular hematological malignancies, and define new therapeutic strategies.

The Ubiquitin Family in Hematologic Malignancies

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.

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.

Figure 2 Blaste leucemique de LAM
Figure 2: AML leukemic blasts

 

 

 

 

 

 

 

 

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

 

Selection of publications related to this theme:

Bossis, G., Sarry, J.E., Kifagi, C., Ristic, M., Saland, E., Vergez, F., Salem, T., Boutzen, H., Baik, H., Brockly, F., Pelegrin, M., Kaoma, T., Vallar, L., Recher, C., Manenti, S., Piechaczyk, M. The ROS/SUMO axis contributes to the response of acute myeloid leukemia cells to chemotherapeutic drugs. Cell Reports 7: 1815-1823 (2014)

 Tempé, D., Vives, E., Brockly, F., Brooks, H., de Rossi, S., Piechaczyk, M. and Bossis, G.  SUMOylation of the inducible (c-Fos:c-Jun)/AP-1 transcriptional complex occurs on target promoters to limit transcription. Oncogene doi: 10.1038/onc.2013.4 (2013)

 Baik, H., Hossein, S-M., Kowalczyk, J., Boulanger, M., Zaghdoudi, S., Salem, T., Sarry, J-E., Hicheri, Y., Cartron, G., Piechaczyk, M. and Bossis, G. Inhibition of the SUMO pathway potentiates all-trans-retinoic acid differentiation of non-promyelocytic acute myeloid leukemia. Cancer Res. doi: 10.1158/0008-5472.CAN-17-336 (2018)

 Gâtel P, Brockly F, Reynes C, Pastore M, Hicheri Y, Cartron G, Piechaczyk M, Bossis G. Ubiquitin and SUMO conjugation as biomarkers of acute myeloid leukemias response to chemotherapies. Life Sci Alliance (2020). 3(6):e201900577

 Gâtel P, Piechaczyk M, Bossis G. Ubiquitin, SUMO, and Nedd8 as Therapeutic Targets in Cancer. Adv Exp Med Biol. (2020) 1233:29-54.

 

Transcriptional control of the aggressiveness of metastatic breast cancers

(Program directed by Isabelle Jariel-Encontre)

 

Transcription factors are essential molecular platforms for the integration of intra- and extracellular signals and their activity is regulated by numerous post-translational modifications. However, the molecular mechanisms by which their deregulation alters gene expression at the chromatin level to allow cancer cells to adapt to their environment and increase their aggressiveness are still poorly understood. This is particularly true for the ubiquitous AP-1 complex which is a group of dimeric transcription factors formed by members of the Fos and Jun multigenic families involved, on the one hand, in the regulation of virtually all cellular and physiological processes and, on the other hand, in the development of many pathologies.

Figure 2: Fos family protein accumulating in the nucleus (yellow) and contrasting with a protein diffusing freely between the nucleus and the cytoplasm (red)
Figure 2: Fos family protein accumulating in the nucleus (yellow) and contrasting with a protein diffusing freely between the nucleus and the cytoplasm (red)

In this context, we are studying (i) why and how two proteins of the c-Fos proto-oncoprotein family, Fra-1 and Fra-2, contribute to the metastatic phenotype and aggressiveness of so-called triple negative breast tumors (TNBCs), where they are overexpressed and hyperphosphorylated due to perverted intracellular signaling, and (ii) to what extent this knowledge may lead to new treatments.

This question is particularly important because metastatic breast tumours are currently the leading cause of cancer death in women.

Our project is based on high-throughput transcriptomic and genomic approaches combined with the exploitation of clinical databases and functional studies of transcription and intracellular signalling. Our goals are to identify Fra-1 and Fra-2 gene targets whose protein products could constitute new pharmacological targets in the treatment of breast cancer and to elucidate the transcriptional mechanisms controlled by Fra-1 and Fra-2 proteins that could be exploited therapeutically when they are abnormally expressed.

Selection of publications related to this theme:

 Malnou CE, Brockly F, Favard C, Moquet-Torcy G, Piechaczyk M, Jariel-Encontre I. Heterodimerization with different Jun proteins controls c-Fos intranuclear dynamics and distribution. J Biol Chem. 285:6552-62. doi: 10.1074/jbc.M109.032680. (2010)

Talotta F, Mega T, Bossis G, Casalino L, Basbous J, Jariel-Encontre I, Piechaczyk M, Verde P. Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene 29:4732-40. doi: 10.1038/onc.2010.211 (2010)

 Sayan, A.E., Stanford, R., Vick ery, R., Grigorenko, E., Diesch, J., Kulbicki, K., Edwards, R., Pal, R., Greaves, P., Jariel-Encontre, I., Piechaczyk, M., Kriajevska, M., Mellon, J.K., Dhillon, A.S., Tulchinsky, E. Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. Oncogene 31: 1493-1503 (2012)

 Belguise, K., Milord, S., Galtier, F., Moquet-Torcy, G., Piechaczyk, M., Chalbos, D. The PKCtheta pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells. Oncogene 31: 4889-4897 (2012)

 Salem T, Gomard T, Court F, Moquet-Torcy G, Brockly F, Forné T, Piechaczyk M. Chromatin loop organization of the junb locus in mouse dendritic cells. Nucl. Acids Res. 41:8908-25. doi: 10.1093/nar/gkt669 (2013)

 Pérez-Benavente B, García JL, Rodríguez MS, Pineda-Lucena A, Piechaczyk M, Font de Mora J, Farràs R. (2013) GSK3-SCF(FBXW7) targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase. Oncogene. 32:2189-99. doi: 10.1038/onc.2012.235 (2013)

 Moquet-Torcy G, Tolza C, Piechaczyk M, Jariel-Encontre I. Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer. Nucleic Acids Res. 42:11011-24. doi: 10.1093/nar/gku814 (2014)

 Tolza C, Bejjani F, Evanno E, Mahfoud S, Moquet-Torcy G, Gostan T, Maqbool MA, Kirsh O, Piechaczyk M, Jariel-Encontre I.  AP-1 Signaling by Fra-1 Directly Regulates HMGA1 Oncogene Transcription in Triple-Negative Breast Cancers. Mol. Cancer Res. 17:1999-2014. doi: 10.1158/1541-7786.MCR-19-0036. (2019)

Bejjani F, Evanno E, Zibara K, Piechaczyk M, Jariel-Encontre I. The AP-1 transcriptional complex: Local switch or remote command? Biochim. Biophys. Acta Rev. Cancer 1872:11-23. doi: 10.1016/j.bbcan.2019.04.003. (2019).

Members

Team leader

Guillaume BOSSIS

Chercheur DR2

(+33) 04 34 35 96 70

216

Dana AKL

Doctorant

+33 (0)4 34 35 96 71

Mays AQROUQ

Stagiaire

+33 (0)4 34 35 96 70

216

MEHULI CHAKRABORTY

Doctorant

+33 (0)4 34 35 96 46

201

Marion DETOLEDO

Chercheur

(+33) 04 34 35 96 71

RDC04

Ludovic GABELLIER

Doctorant

+33 (0)4 34 35 96 71

201

Rawan HALLAL

Doctorant

+33 (0)4 34 35 96 70

216

Isabelle JARIEL

Chercheur

(+33) 04 34 35 96 68

216

Maia MARCHAND

Stagiaire

+33 (0)4 34 35 96 70

216

Marc PIECHACZYK

Chercheur DR1

(+33) 04 34 35 96 68

216 - 201

Clara RECASENS-ZORZO

Post-Doc

+33 (0)4 34 35 96 68

214

Denis TEMPE

Chercheur

+33 (0)4 34 35 96 71

216

Selected Publications

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Funding

 

 

Interactions

 

 

 

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