- MDS/MPN syndromes
- Acute Myeloid Leukemia (AML)
- Myelodysplastic Syndromes (MDS)
- Axis 1: Identification of therapeutic targets and development of innovative molecules in MDS and AML
- Axis 2: Dissecting and targeting the mechanism involved in the generation of immunosuppressive myeloid cells
- Targeted therapy
- Immunotherapy
- Alternative therapy
- Chemotherapy
The team has a longstanding expertise in the study of cell death and autophagy pathways and BH3-profiling on hematopoietic cells (AML, MDS, CMML, LMC). Notably, the team has also contributed to uncouple apoptosis from differentiation mechanisms.
Scientific
- Role of Bcl-2 family members in hematopoietic malignancies: Bcl-2 family members plays a key role in the regulation of cell fate by fine-tuning the cell death/survival balance and BH3 peptidomimetics targeting Bcl-2 have successfully joined the armamentarium of anti-leukemic drugs. We showed that Bcl-B plays a key role in plasma cell differentiation and identified its high expression as a marker of bad prognosis in MM. We discovered that overexpression of Bcl-B in the B cell lineage triggers a murine disease that recapitulates MM. We also identified that phosphorylation of Bim by Lyn inhibits its pro-apoptotic activity. In collaborative studies using large scale BH3 profiling, we confirm the interest of Bcl-2 and Mcl-1 targeting in different types of leukemia. Our findings highlighted the role of Bcl-2 family proteins in regulating apoptosis and differentiation of hematopoietic cells and confirm the interest of BH3 profiling for individual patients
- Reprogramming of macrophages as a therapeutic strategy in inflammation and cancer: We established that caspases and cathepsins are necessary for the physiological differentiation of human monocytes into macrophages. We also demonstrated that caspase activation is necessary for IL-4 mediated polarization of macrophages and showed that Emricasan, a clinically given pan-caspase inhibitor reprograms anti- into pro-inflammatory macrophages
- Targeting autophagy in myeloid malignancies: Autophagy plays an essential role in the differentiation of hematopoietic cells and alterations of autophagy are associated with the pathogenesis of myeloid malignancies. Targeting different modes of autophagy including macro (MA) and chaperone-mediated autophagy (CMA) thus, appears as attractive strategies in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this line, we have shown that low level of LAMP2 expression is a marker of poor prognosis in MDS and AML patients. To explore the role of LAMP2 in vivo and to determine whether mice deleted for both MA and CMA are prone to develop myeloid malignancies, we invalidated LAMP2 in the hematopoietic system and in the myeloid compartment and are now analyzing the phenotype of these mice. Recently we also provided the proof of concept that CMA could be highjacked to degrade specific oncoproteins such as FLT3/ITD and Bcr/Abl
- Targeting proteostasis and metabolism in cancers: Targeting proteostasis and metabolism is of outmost interest for cancer therapy. With Team 12 (S. Rocchi et T. Passeron, C3M), we used click-chemistry approaches to target cellular vulnerabilities in MDS and AML. We developed HA-344 as a dual covalent inhibitor of IMPDH and PKM2, 2 important metabolic vulnerabilities in cancer cells. We also established that HA-344 is a potent inducer of ferroptosis in MDS and AML cell lines and identified GPX4 as a new target of this drug.
Medical
- Thomas Cluzeau builds a bid clinical research unit allowing to propose at our patients more than 80 phase 1 to 4 clinical trials. I coordinate some academic and industrial clinical trials leading publications in A and A+ journal like NEJM, Lancet, JCO and Leukemia. I am working on translational projects with INSERM U1065 (VENETACIBLE) and other entities like mathematics faculty in the MDS and AML area
- Michael Loschi is a transplant physician at Nice University Hospital, a member of the board of the French Society of bone marrow transplantation and cell therapy, principal investigator in 30 clinical trials on myelofibrosis, stem cell transplantation and bone marrow failure in the last 5 years. He also developed a translational research program on immunomodulation post cellular therapy
- Chaintreuil P, Kerreneur E, Bourgoin M, Savy C, Favreau C, Robert G, Jacquel A, Auberger P. The generation, activation, and polarization of monocyte-derived macrophages in human malignancies.
Front Immunol. 2023 Apr 18;14:1178337. doi: 10.3389/fimmu.2023.1178337. eCollection 2023. PMID: 37143666 Free PMC article. Review.
- Platzbecker U, Della Porta MG, Santini V, Zeidan AM, Komrokji RS, Shortt J, Valcarcel D, Jonasova A, Dimicoli-Salazar S, Tiong IS, Lin CC, Li J, Zhang J, Giuseppi AC, Kreitz S, Pozharskaya V, Keeperman KL, Rose S, Shetty JK, Hayati S, Vodala S, Prebet T, Degulys A, Paolini S, Cluzeau T, Fenaux P, Garcia-Manero G. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023 Jul 29;402(10399):373-385. doi: 10.1016/S0140-6736(23)00874-7. Epub 2023 Jun 10. PMID: 37311468 Clinical Trial.
- Aid Z*, Robert E*, Lopez CK*, Bourgoin M, Boudia F, Le Mene M, Riviere J, Baille M, Benbarche S, Renou L, Fagnan A, Thirant C, Federici L, Touchard L, Lecluse Y, Jetten A, Geoerger B, Lapillonne H, Solary E, Gaudry M, Meshinchi S, Pflumio F, Auberger A, Lobry C, Petit A*, Jacquel A*, Mercher T*. High Caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2:GLIS2 pediatric leukemia. Leukemia. 2022 Dec 30. In press. *equal contribution
- Lin KH*, Rutter JC*, Xie A, Killarney ST, Vaganay C, Benaksas C, Ling F, Sodaro G, Meslin PA, Bassil CF, Fenouille N, Hoj J, Washart R, Ang HX, Cerda-Smith C, Chaintreuil P, Jacquel A, Auberger P, Forget A, Itzykson R, Lu M, Lin J, Pierobon M, Sheng Z, Li X, Chilkoti A, Owzar K, Rizzieri DA, Pardee TS, Benajiba L, Petricoin E, Puissant A*, Wood KC*. P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nat Cancer. 2022 Jun 6. *Equal contribution.
- Cluzeau T, Sebert M, Rahmé R, Cuzzubbo S, Lehmann-Che J, Madelaine I, Peterlin P, Bève B, Attalah H, Chermat F, Miekoutima E, Rauzy OB, Recher C, Stamatoullas A, Willems L, Raffoux E, Berthon C, Quesnel B, Loschi M, Carpentier AF, Sallman DA, Komrokji R, Walter-Petrich A, Chevret S, Ades L, Fenaux P. Eprenetapopt Plus Azacitidine in TP53-Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM). J Clin Oncol. 2021 May 10;39(14):1575-1583. doi: 10.1200/JCO.20.02342. Epub 2021 Feb 18. PMID: 33600210 Free PMC article. Clinical Trial.
- Zerhouni M, Martin A, Furstoss N, Gutierrez V, Jaune E, Tekaya N, Beranger G, Abbe P, Regazzetti C, Amdouni H, Driowya M, Dubreuil P, Luciano F, Jacquel A, Tulic M, Cluzeau T, O'Hara B, Ben-Sahra I, Passeron T, Benhida R, Robert G*, Rocchi, S* and Auberger, P*, Dual covalent inhibition of PKM and IMPDH targets metabolism in cutaneous metastatic melanoma. Cancer Res. 2021 Jun 7: canres.2114.2020.
- Courjon J, Dufies O, Robert A, Bailly L, Torre C, Chirio D, Contenti J, Vitale S, Loubatier C, Doye A, Pomares-Estran C, Gonfrier G, Lotte R, Munro P, Visvikis O, Dellamonica J, Giordanengo V, Carles M, Yvan-Charvet L, Ivanov S, Auberger P, Boyer L*, Jacquel A*. Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity. Blood Adv. 2021 Mar 9;5(5):1523-1534. * Equal contribution.
- Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, Finelli C, Cazzola M, Ilhan O, Sekeres MA, Falantes JF, Arrizabalaga B, Salvi F, Giai V, Vyas P, Bowen D, Selleslag D, DeZern AE, Jurcic JG, Germing U, Götze KS, Quesnel B, Beyne-Rauzy O, Cluzeau T, Voso MT, Mazure D, Vellenga E, Greenberg PL, Hellström-Lindberg E, Zeidan AM, Adès L, Verma A, Savona MR, Laadem A, Benzohra A, Zhang J, Rampersad A, Dunshee DR, Linde PG, Sherman ML, Komrokji RS, List AF. N Engl J Med. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. 2020 Jan 9;382(2):140-151. PMID: 31914241 Clinical Trial.
- Jacquel A*, Hospital MA*, Mazed F*, Saland E, Larrue C, Mondesir J, Birsen R, Green AS, Lambert M, Sujobert P, Gautier EF, Salnot V, Le Gall M, Decroocq J, Poulain L, Jacque N, Fontenay M, Kosmider O, Récher C, Auberger P, Mayeux P, Bouscary D, Sarry JE, Tamburini J. RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia. Leukemia. 2018 Mar;32(3):597-605. * Equal contribution. Auberger P, Puissant A. Autophagy, a key mechanism of oncogenesis and resistance in leukemia. Blood. 2017 Feb. 2;129(5):547-552. PMID: 27956388. P, D, C.
- Hamouda MA, Jacquel A, Robert G, Puissant A, Richez V, Cassel R, Fenouille N, Roulland S, Gilleron J, Griessinger E, Dubois A, Bailly-Maitre B, Goncalves D, Mallavialle A, Colosetti P, Marchetti S, Amiot M, Gomez-Bougie P, Rochet N, Deckert M, Avet-Loiseau H, Hofman P, Karsenti JM, Jeandel PY, Blin-Wakkach C, Nadel B, Cluzeau T, Anderson KC, Fuzibet JG, Luciano F* Auberger P*, BCL-B (BCL2L10) is overexpressed in patients suffering from multiple myeloma (MM) and drives an MM-like disease in transgenic mice. J Exp Med. 2016 Aug 22;213(9):1705-22.
