U1131 Team 1

Team 1 is directed by S. Giraudier and gathers 5 groups dedicated to a translational research in myeloproliferative disorders (MPNs and JMML) with specific skills in foetal hematopoiesis, epigenetics and animal models. 

 

Group 1: Stephane Giraudier (MD, PhD), Jean-Jacques Kiladjian (MD, PhD), Bruno Cassinat (PharmD, PhD), Nabih Maslah (PharmD, PhD)

Our team aims at delineating the mechanisms of BCR-ABL1 negative myeloproliferative neoplasms (MPNs) emergence and evolution. Leaders of this team are dedicated to both clinical and biological management of MPNs since more than 20 years and are the head of the Integrated Center for MPNs at Saint-Louis hospital (http://hopital-saintlouis.aphp.fr/centre-integre-des-neoplasies-myelopro...). In the recent years we have addressed several aspects of the disease (places of molecular alterations in MPNs, role of the JAK2V617F mutation in endothelial cells, identification of senescence as a new therapeutic option with IFN alone or in combination with arsenic) and initiated or participated to several clinical trials in MPNs.

Models dedicated to a translational research for a better understanding and management of MPNs: Patients samples, patients-derived cell lines, patients-derived induced pluripotent stem cells (iPSC), murine models (transgenic and transplantable), primary cell cultures, next generation sequencing, lentiviral transduction, cell sorting and microfluidic single cell DNA analysis.

Currently our projects are focusing on the modeling of normal and pathological (JAK2V617F mutated) stress hematopoiesis, the bone marrow microenvironment of MPN patients, and the relation between clonal selection and patients’ outcome or response to treatment.

 

Group 2: Fabien Guidez (CRCN, PhD), and Patricia Krief (CRHC, PhD).

F. Guidez is the Director of the MaNEP epigenetic platform labelized Aviesan. After 15 years, in the US and the UK as a postdoc and team leader (Recipient of LRF Bennet Fellowship in 2003), he joined the U1131 unit to develop his research on the regulation of Heterochromatin formation and maintenance in normal and cancer cells.

As abnormal epigenetic landscapes and mutations in the epigenetic machinery are increasingly associated in diseases/cancer and largely influenced by environmental exposures, we have recently developed new technologies to assess their impact on pathogenic mechanisms. These technologies are developed to address issues of scarce samples at diagnosis and during disease progression and treatment (biomarker/surrogate marker monitoring) as also preclinical studies (in vitro and in vivo). We are studying several epigenetic regulators (e.g. CBP, TET2, ASXL1, EZH2 or DNMT3A) in the context of several hematopoietic diseases, and also the role of the stem cell epigenetic factor PLZF (essential for germ cells and hematopoietic stem cells maintenance). Our main project is to understand the impact of the dysregulation of epifactors by chemical/environmental exposures (e.g. benzene) or specific mutations, and to characterize their effects on stem cell epigenetic patterning and on heterochromatin/retrotransposon regulation.

 

The group is now focusing on:

-  establishing the role of epigenetic regulation in the protection of stem cells to environmental stress

-  describing the differential gene expression triggered by differentiating drugs and epigenetic agents on epigenetic regulators and stem cell genes

-  identifying novel disease/safety biomarkers, characterizing epigenetic signatures for drugs or environmental xenobiotics in order to assess oncogenic risks

 

Group 3 : Rose Ann Padua (Emeritus Director of Research, Ph.D) previously Reader at the University of Wales College, UK of Medicine and Deputy Director of the Leukemia Research Fund Preleukemia Unit. As a Fulbright scholar, spent 18 months in the laboratories of the Nobel Laureate Michael Bishop at the University of California San Francisco, USA; was a Consultant Clinical Scientist with the NHS at King's College Hospital in London, UK, where as the Head of the Minimal Residual Disease Section she set up their molecular diagnostics program for adult leukemia; is a molecular biology consultant for the UN’s International Atomic Energy Agency. Previously Chair of Working Group on novel therapies of European COST action and animal models Work Package for the European Leukemia Network. 

Her research focus has been on developing animal models to understand the biology of myeloid malignancy and to use these as preclinical tools to evaluate targeted therapeutic options.  The most innovative of the approaches under development is a DNA based immunotherapy strategy.

 

Group 4 : Michèle Souyri (DR Inserm) “Hematopoietic stem cells (HSC) and stromal development during human embryogenesis : application to pediatric ALL”

Our group is interested in deciphering the cellular and molecular events controlling hematopoietic stem cells (HSCs) generation and amplification of adult-type in the fetal liver (FL) and bone marrow (FBM) during the first two trimester of human development.

The cross-talk between HSCs and stromal cells of the various niches during development has also an important impact on HSCs features. To get further insights into the biology of fetal HSC, we therefore established stromal cells cultures derived from human FL and FBM at, and from pediatric/young adults BM. Phenotypical, molecular (RNA seq) and functional characterization, together with the comparison of their respective capacity to sustain long-term hematopoiesis and promote HSC expansion, is under study.

We translated this fundamental research to pediatric diseases such as Fanconi Anemia (collaboration with Pr J. Soulier) and JMML, in collaboration with the group of Dr Hélène Cavé in our unit, and now to pediatric B-ALL, in collaboration with the team of Dr Halfon-Domenech (IHOPe/CRCL, Lyon)

 

Group 5: Hélène Cavé (PUPH), Aurélie Caye (PH), Elodie Lainey (MCU-PH), Marion Strullu (MCU-PH)

Our research interests stem directly from our hospital activities on developmental diseases and paediatric leukaemia at the Robert Debré Children's Hospital, with a focus on 1) germline and somatic diseases associated with pathological RAS/MAPK activation, e.g. RASopathies and juvenile myelomonocytic leukemia (JMML), and 2) the link between ontogeny and leukemogenesis in childhood leukemia.

JMML is a rare myeloproliferative and myelodysplastic neoplasm that occurs in infants and young children and is considered a model of RAS-driven oncogenesis. Our works contribute to uncover and describe JMML-predisposing genetic conditions (e.g. Noonan syndrome, CBL syndrome) and to better understand JMML leukemogenesis.

By studying the genetic landscape of JMML, we have highlighted the critical role of a limited number of pathways including the PRC2 and RAS, further underlining the privileged association between RAS signaling and JMML leukemogenesis. By combining genetic and cellular approaches and xenotransplantation models, (coll D Bonnet, Crick’s Institute), we then sought to identify the leukemia initiating cell within the hematopoietic hierarchy, and also within ontogeny (coll. M Souyri). Indeed, the early and specific age window of onset of this leukemia argues in favor a role for developmental hematopoiesis. Our hypothesis is that some of the fetal physiological characteristics of haematopoiesis, either endogenous to the hematopoietic cells and/or originating from the microenvironnement, are subverted in infant leukaemogenesis. Through these studies we hope to help design new therapeutic approaches in this dreadful leukaemia but also to gain a better understanding of RAS-driven oncogenesis.

 

Our research works are conducted in collaboration with the Genetics and Pediatric Hematology-Oncology units of Robert Debré Hospital and with national and international networks in the field of leukemia (I-BFM, ESHLO, TRANSCALL) or RASopathies (NS_Euronet).

 

References group 1 :

Dagher T*, Maslah N*, Edmond V*, Cassinat B, Vainchenker W, Giraudier S, Pasquier F, Verger E, Niwa-Kawakita M, Lallemand-Breitenbach V, Plo I, Kiladjian JJ#, Villeval JL#, de Thé H#. JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML. J Exp Med. 2021 Feb 1;218(2):e20201268. PMID: 33075130 (* and # participated equally)

Gisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, Rossiev V, Dulicek P, Illes A, Pylypenko H, Sivcheva L, Mayer J, Yablokova V, Krejcy K, Grohmann-Izay B, Hasselbalch HC, Kralovics R, Kiladjian JJ; PROUD-PV Study Group. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020 Mar;7(3):e196-e208. PMID: 32014125

Debureaux PE, Cassinat B, Soret-Dulphy J, Mora B, Verger E, Maslah N, Plessier A, Rautou PE, Ollivier-Hourman I, De Ledinghen V, Goria O, Bureau C, Siracusa C, Valla D, Giraudier S, Passamonti F, Kiladjian JJ. Molecular profiling and risk classification of patients with myeloproliferative neoplasms and splanchnic vein thromboses. Blood Adv. 2020 Aug 11;4(15):3708-3715. PMID: 32777065

 

Maslah N, Salomao N, Drevon L, Verger E, Partouche N, Ly P, Aubin P, Naoui N, Schlageter MH, Bally C, Miekoutima E, Rahmé R, Lehmann-Che J, Ades L, Fenaux P, Cassinat B, Giraudier S. Synergistic effects of PRIMA-1Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2020 Jun;105(6):1539-1551. PMID: 31488557

Guadall A, Lesteven E, Letort G, Awan Toor S, Delord M, Pognant D, Brusson M, Verger E, Maslah N, Giraudier S, Larghero J, Vanneaux V, Chomienne C, El Nemer W, Cassinat B, Kiladjian JJ .Endothelial Cells Harbouring the JAK2V617F Mutation Display Pro-Adherent and Pro-Thrombotic Features. Thromb Haemost. 2018 Sep;118(9):1586-1599. PMID: 30103245

Besancenot R, Chaligné R, Tonetti C, Pasquier F, Marty C, Lécluse Y, Vainchenker W, Constantinescu SN, Giraudier S. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol. 2010 Sep 7;8(9):e1000476. PMID: 20838657

Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, Bellucci S, Grandchamp B, Chomienne C, Fenaux P. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008 Oct 15;112(8):3065-72. PMID: 18650451

 

References group 2:

Zhang W, Berthelet J, Michail C, Bui LC, Gou P, Liu R, Duval R, Renault J, Dupret JM, Guidez F, Chomienne C, Rodrigues Lima F. Human CREBBP acetylstranferase is impaired by etoposide quinone, na oxidative and leukemogenic metabolite of the anticâncer drug etoposide through modification of redox-sensitive zinc-finger cysteine residues (2020). Free Radic Biol Med, 5849(20):31640-3

Duval R, Bui LC, Mathieu C, Nian Q, Berthelet J, Xu X, Haddad I, Vinh J, Dupret JM, Busi F, Guidez F, Chomienne C, Rodrigues-Lima F. Benzoquinone, a leukemogenic metabolite of benzene, catalycatelly inhibits the protein tyrosine phosphatase PTPN2 and alters STAT1 signaling (2019). J Biol Chem. 294(33):12483-12494

Nian Q, Berthelet J, Zhang W, Bui LC, Liu R, Xu X, Duval R, Ganesan S, Leger T, Chomienne C, Busi F, Guidez F, Dupret JM, Rodrigues Lima F. T-Cell Protein Tyrosine Phosphatase is irreversibly inhibited by etoposide-quinone, a reactive metabolite of the chemotherapy drug etoposide (2019). Mol Pharmacol 96(2): 297-306

 

Domenech C, Maillard L, Rousseau A, Guidez F, Petit L, Pla M, Clay D, Guimiot F, Sanfilippo S, Jacques S, de la Grange P, Robil N, Soulier J, Souyri M. Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi  anemia (2018). Stem Cell Reports 11(5):1075-1091

 

Guerenne L, Beurlet S, Said M, Gorombei P, Le Pogam C, Guidez F, de la Grange P, Omidvar N, Vanneaux V, Mills K, Mufti GJ, Sarda-Mantel L, Noguera ME, Pla M, Fenaux P, Padua RA, Chomienne C, Krief P. GEP analysis validates high risk MDS and acute myeloid leukelia post MDS mice models and highlights novel dysregulated pathways (2016). J Hematol Oncol. 27;9:5

 

Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, Fenneteau O, Lainey E, Nouri K, Nakhaei-Rad S, Dvorsky R, Lachenaud J, Pereira S, Vivent J, Verger E, Vidaud D, Galambrun C, Picard C, Petit A, Contet A, Poirée M, Sirvent N, Méchinaud F, Adjaoud D, Paillard C, Nelken B, Reguerre Y, Bertrand Y, Häussinger D, Dalle JH, Ahmadian MR, Baruchel A, Chomienne C, Cavé H. Juvenile myelomonocytic leukemia displays mutations in components ot the RAS pathway and the PRC2 network (2015). Nat Genet. 47 (11):1334-40.

McConnell MJ, Durand L, Langley E, Coste-Sarguet L, Zelent A, Chomienne C, Kouzarides T, Licht JD, Guidez F. Post Transcriptional control of the epigenetic stem cell regulator PLZF by Sirtuin and HDAC deacetylases (2015). Epigenetics Chromatin 24;8:38.

Puszyk W, Down T, Grimwade D, Chomienne C, Oakey RJ, Solomon E & Guidez F. The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells (2013). EMBO J., 32: 1941-52.

 

He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A and Pandolfi PP.  Aberrant interactions of PML-RARa and PLZF-RARa with transcriptional co-repressors determine differential responses to retinoic acid in APL (1998).  Nature Genetics 18; 126-135.

 

References Group 3 :

Le Goff S, Boussaid I, Floquet C, Raimbault A, Hatin I, Andrieu-Soler C, Salma M, Leduc M, Gautier E-F, Boris Guyot,  D'Allard D, Montel N, Ducamp S, Houvert A,  Guillonneau F , Giraudier S, Cramer-Borde E, Morle F, Diaz J-J, Hermine O, Taylor N, Kinet S, Verdier F, Padua RA,  Narla M, Gleizes P-E, Soler E, Mayeux P, Fontenay M. p53 activation during ribosome biogenesis regulates normal erythroid differentiation. Blood, 2020 accepted. PMID: 32818241

Omidvar N, Tekin N, Conget P, Brunac F, Timar B, Gagyi E, Basak R, Auewarakul C, Sritana N, Cerci JJ,  Dimamay MP, Gyorke T, Redondo F, Nair R, Gorospe C, Paez D, Fanti S,  Ozdag H, Padua RA, Carr R. Identification of a Patient Cohort with Relapsing Diffuse Large B-Cell Lymphoma with a Low International Prognostic Index in PET/CT Using a 2-Gene (LMO2/TNFRSF9) Scoring System. Acta Hematologica 2020 DOI: 10.1159/000505605. PMID:32187599

Guerenne L, Beurlet S, Said M, Gorombei P, Le Pogam C, Guidez F, de la Grange P, Omidvar N, Vanneaux V, Mills K, Mufti GJ, Sarda-Mantel L, Noguera M-E, Pla M, Fenaux P, Padua RA, Chomienne C, Krief P. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways. J Hematol Oncol. 9: 5, 2016. PMID:26817437

Le Pogam C, Patel S, Gorombei P, Guerenne L, Krief P, Bernasconi E, Tekin N, Sicre F, Schlageter M-H, Chopin M, Mathews V, West RR, PLA M, Fenaux P, Chomienne C, Padua RA. DNA-mediated immunotherapy induces immune responses and extends life-span in two different mouse models of myeloid malignancies. Oncotarget 6:32494-508, 2015. PMID:26378812

Beurlet S, Omidvar N,Gorombei P, Krief P, Le Pogam C, Setterblad N, de la Grange P, Leboeuf C, Janin A,Noguera M-E, Hervatin F, Sarda-Mantel L, Konopleva M, Andreeff M, Tu A, Fan AC, Felsher DW, Whetton A, Pla M, West R, Fenaux P, Chomienne C, Padua RA. BCL-2 inhibition with ABT-737 prolongs survival in an NRAS/BCL-2 mouse model of AML by targeting primitive LSK and progenitor cells. Blood 122: 2864-2876, 2013. PMID:23943652

Furugaki K, Pokorna K, Le Pogam C, Aoki M, Reboul M, Bajzik V, Krief P, Janin A, Noguera ME, West R, Charron D, Chomienne C, Pla M, Moins-Teisserenc H, Padua RA. DNA vaccination with all-trans retinoic acid treatment induces long-term survival and elicits specific immune responses requiring CD4+ and CD8+ T-cell activation in an acute promyelocytic leukemia mouse model. Blood 15:653-6, 2010. PMID:19965687

Fan AC, Deb-Basu D, Orban MW, Gotlib JR, Natkunam Y, O'Neill R, Padua RA, Xu L, Taketa D, Shirer AE, Beer S, Yee AX, Voehringer DW, Felsher DW. Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens. Nature Medicine 15:566-571, 2009. PMID:19363496

 

References group 4 :

Maillard L., Sanfilippo S., Domenech C., Kasmi N., Petit L., Jacques S., Delezoide A.L., Guimiot F., Eladak S., Moison D., Nicolas N., Rouiller-Fabre V., Pozzi-Godin S., Mennesson B., Brival M.L., Letourneur F., Jaffredo T., Chomienne C. and Souyri M. CD117hi expression distinguishes a new human fetal HSC population with high proliferation and self-renewal potential. Haematologica, 2020, 105:e43-47.

Hacein-Bey-Abina S, Estienne M, Bessoles S, Echchakir H, Pederzoli-Ribeil M, Chiron A, Aldaz-Carroll L, Leducq V, Zhang Y, Souyri M, Louache F, Abina AM. Erythropoietin is a major regulator of thrombopoiesis in thrombopoietin-dependent and -independent contexts. Exp Hematol. 2020 88:15-27.

Yvernogeau L, Gautier R, Petit L, Khoury H, Relaix F, Ribes V, Sang H, Charbord P, Souyri M, Robin C, Jaffredo T. In vivo generation of haematopoieticstem/progenitor cells from bone marrow-derived haemogenic endothelium. Nat Cell Biol. 2019 Nov;21(11):1334-1345.

Domenech C., Maillard L., Rousseau A., Guidez F., Petit L., Pla M., Clay D., Guimiot F., Sanfilippo S., Jacques S., de la Grange P., Robil N., Soulier J., and Souyri M. Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia. Stem Cell Reports, 2018, 11:1075-1091.

Petit-Cocault L., Fleury M., Clay D., Larghero J, Vanneaux V. and Souyri M. Monoclonal antibody 1.6.1 against human MPL receptor allows HSC enrichment of CB and BM CD34+CD38− populations. Exp Hematol, 2016, 44: 297-302.

 

References group 5 :

 A Caye°, K Rouault-Pierre°, M Strullu°, E Lainey, A Abarrategi, O Fenneteau, C Arfeuille, J Osman, B Cassinat, S Pereira, F Anjos-Afonso, E Currie, L Ariza-McNaughton, V Barlogis, J-H Dalle, A Baruchel, C Chomienne, H Cavé* and D Bonnet*. Despite mutation acquisition in hematopoietic stem cells, JMML propagating cells are not always restricted to this compartment. Leukemia 2020, Jun;34(6):1658-1668

 

M Stanulla, H Cavé, AV Moorman for the International BFM Study Group (I-BFM-SG). IKZF1 deletions in pediatric acute lymphoblastic leukemia: still a poor prognostic marker? Blood 2020 Jan 23;135(4):252-260

 

C Piette, S Suciu, E Clappier, Y Bertrand, S Drunat, S Kagialis-Girard, K Yakouben, G Plat, N Dastugue, F Mazingue, N Grardel, N Van Roy, A Uyttebroeck, V Costa, O Minckes, N Sirvent, P Simon, P Lutz, A Ferster, C Pluchart, M Poirée, C Freycon, MF Dresse, F Millot, C Chantrain, J Van der Werff Ten Bosch, K Norga, C Gilotay, PS Rohrlich, Y Benoit, and H Cavé. Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukemia: results of the EORTC CLG 58881 and 58951 trials. Leukemia. 2017 Jan;32(1):244-248

 

H Cavé, A Caye, N Ghedira, Y Capri, N Pouvreau, N Fillot, A Trimouille, C Vignal, O Fenneteau, Y Alembik, JL Alessandri, P Blanchet, O Boute,  P Bouvagnet, A David, A Dieux Coeslier, B Doray, O Dulac, V Drouin-Garraud, M Gérard, D Héron, B Isidor, D Lacombe, S Lyonnet, L Perrin, M Rio, J Roume, S Sauvion, A Toutain, C Vincent-Delorme, M Willems, C Baumann, A Verloes. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia. Eur J Hum Genet. 2016 Aug;24(8):1124-31

 

Caye A, Strullu M, Guidez F, Cassinat B, Gazal S, Fenneteau O, Lainey E, Nouri K, Nakhaei-Rad S, Dvorsky R, Lachenaud J, Pereira S, Vivent J, Verger E, Vidaud D, Galambrun C, Picard C, Petit A, Contet A, Poirée M, Sirvent N, Méchinaud F, Adjaoud D, Paillard C, Nelken B, Reguerre Y, Bertrand Y, Häussinger D, Dalle JH, Ahmadian MR, Baruchel A, Chomienne C, Cavé H. Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet. 2015 Nov;47(11):1334-40

 

M Strullu, A Caye, J Lachenaud, B Cassinat, S Gazal, O Fenneteau, N Pouvreau, S Pereira, C Baumann, A Contet, N Sirvent, F Méchinaud, I Guellec, D Adjaoud, C  Paillard, C Alberti, M Zenker, C Chomienne, Y Bertrand, A Baruchel, A Verloes, H Cavé. Juvenile myelomonocytic leukaemia and Noonan Syndrome. J Med Genet 2014 Oct;51(10):689-97

 

E Flex, M Jaiswal, F Pantaleon, S Martinelli, M Strullu, EK Fansa, A Caye, A De Luca, F Lepri, R Dvorsky, L Pannone, S Paolacci, SC Zhang, V Fodale, G Bocchinfuso, C Rossi, EMM Burkitt-Wright, A Farrotti, E Stellacci, S Cecchetti, R Ferese, L Bottero, E Di Schiavi, O Fenneteau, B Brethon, M Sanchez, AE Roberts, HG Yntema, I van der Burgt, P Cianci, ML Bondeson, MC Digilio, G Zampino, B Kerr, Y Aoki, ML Loh, A Palleschi, A Carè, A Selicorni, B Dallapiccola, IC Cirstea, L Stella, M Zenker, BD Gelb, H Cavé*, MR Ahmadian* & M Tartaglia*. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014 Aug 15;23(16):4315-27.

 

B Pérez, F Mechinaud , C Galambrun, N Ben Romdhane, B Isidor, N Philip, J Derain-Court, B Cassinat, J Lachenaud, S Kaltenbach, A Salmon, C Désirée, S Pereira, ML Menot, N Royer, O Fenneteau, A Baruchel, C Chomienne, A Verloes, H Cavé. Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukemia (JMML). J Med Genet 2010 Oct;47(10):686-91