Inserm, CNRS, Université de Lille, CHU Lille, Institut Pasteur de Lille
Hematological malignancies such as acute myeloid leukemia (AML) and multiple myeloma (MM) arise, reside and evolve in the bone marrow niche. A better understanding of the factors of persistence of tumor cells and the interactions with the tumor microenvironment (TME) is of utmost importance. In recent years, improvements in the treatment of hematological malignancies, notably targeted therapies and new generations immunotherapies, have led to deep and prolonged responses. However, patients still ultimately relapse. This is particularly true in both AML and MM, which are associated with poor clinical outcomes, despite the fact that patients often reach negative minimal residual disease (MRD) after initial treatment. This suggests that rare malignant cells are able to persist within the bone marrow niche and induce disease relapse. Two main factors dictate whether a patient will respond or not to a given treatment. Firstly, factors largely tumor-dependent, such as the clonal evolution and plasticity of malignant cells, escaping the treatment efficacy and inducing the emergence of resistant sub-clones at relapse. Secondly, the immune system is largely patient- and tumor-dependent, capable of recognizing and subsequently acting on the immunogenicity of the tumor. Notably, tumors accumulate mutations over time leading to the generation of neoantigens. In addition, these neoantigens have to be presented in an immunogenic rather than in an immunosuppressive environment for an effective antitumor immune response to occur. In our team project, we combine single cell genomics, transcriptomics, multiplex tissue immunophenotyping and functional assays to investigate how the different components of the marrow environment counteract or support clonal evolution and plasticity of malignant cells under different modalities of leukemia/myeloma treatments. The ultimate goal is to identify novel strategies to modulate dysfunctional interactions and improve durable tumor remission.
This is studied through 2 different axis:
Unravelling the role of molecular plasticity in cancer cells persistence.
In this first aim, we are taking advantage of large datasets of patients with AML and MM available in our lab, through cohorts and clinical trials coordinated at Lille University Hospital. How small subsets of tumor cells are able to escape the treatment efficacy while the bulk of tumor cells are eradicated ? To address this question we are focusing our research on three different aspects :
Axis 1A. Determining the role of stem-like plasticity of tumor cells in AML and MM.
Axis1B. Phylogeny and clonal evolution of neoantigens during immunotherapies.
Axis 1C. Refining molecular classification and MRD in AML and MM.
Advancing cancer immunotherapy: dissecting tumor microenvironment interactions and enhancing synthetic immune responses.
In this second aim, building on our translational clinical research and cancer cell biology insights from Aim 1, we now focus on using findings from clinical trials to enhance immunotherapy strategies. This effort involves a deeper exploration of the interactions between cancer cells and the tumor microenvironment (TME), aiming to refine and improve the dynamics of tumor-immune interactions for more effective treatment outcomes.
Axis2A. Exploiting the chemical TME to design synthetic cytokines with enhanced therapeutic potential.
Axis2B. Assessing the impact of TME on CAR-T cell and bispecific antibodies in myeloma and lymphoma.
Axis2C. Investigating the interplay between endogenous and synthetic immunity, focusing on the role of epitope spreading in maintaining immune responses against cancer.
Main publications
2026
Titah, S., Guillemette, A., Lewuillon, C., Shaik, F. A., Berthon, C., Goursaud, L., Tardivel, M., Bongiovanni, A., Chauvet, P., Jouy, N., Peyrouze, P., Cheok, M., Brinster, C., Manier, S., Tarhan, M. Ç., Lemonnier, L., Quesnel, B., & Touil, Y. (2026). Pre-therapeutic bone marrow-resident leukemic cells in acute myeloid leukemia exhibit a distinct dysregulated calcium signature and stem-like profile reflecting minimal residual disease precursors. Journal of Experimental & Clinical Cancer Research, 45(1), 55. https://doi.org/10.1186/s13046-025-03634-x
Chalopin, T., Cellerin, E., Demarquette, H., Pieragostini, A., Sonntag, C., Jaquet, C., De Wyngaert, Z., Rumpler, A., Roussel, M., Labouré, G., Morel, V., Vincent, L., Salle, V., Cazaubiel, T., Bobin, A., Schavgoulidze, A., Corre, J., Leleu, X., & Manier, S. (2025). Debulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: A retrospective cohort study. Blood Cancer Journal, 15(1), 174. https://doi.org/10.1038/s41408-025-01365-y
Cheng, W., Gaggero, S., Hasan Bou Issa, L., Ouelkdite, A., Escure, G., Cozzani, A., Njosse Tchantchou, Y., Carlier, N., Wauquier, E., Decool, G., Tilmont, R., Podvin, B., Leprohon, M., Fléchon, L., Kasprowicz, A., Groux-Degroote, S., Moreaux, J., Arnulf, B., Corre, J., … Manier, S. (2025). Inflammatory microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma. MedRxiv. https://doi.org/10.1101/2025.04.23.25325569
Manier, S., Lambert, J., Hulin, C., Macro, M., Laribi, K., Araujo, C., Pica, G. M., Touzeau, C., Godmer, P., Slama, B., Karlin, L., Orsini Piocelle, F., Dib, M., Sanhes, L., Morel, P., El Yamani, A., Tiab, M., Tabrizi, R., Richez, V., … Facon, T. (2025). Safety and efficacy of a dexamethasone-sparing regimen with daratumumab and lenalidomide in patients with frailty and newly diagnosed multiple myeloma (IFM2017-03): A phase 3, open-label, multicentre, randomised, controlled trial. The Lancet Oncology, 26(10), 1323–1333. https://doi.org/10.1016/S1470-2045(25)00280-3
Ben Dhia L, Wemeau M, Fenwarth L, Marceau-Renaut A, Fournier E, Ducourneau B, Tricot S, Deschildt M, Huchette P, Darre S, Benhalima I, Margat E, Bories C, Dufossé M, Boyer T, Paubelle E, Charbonnier A, Lebon D, Hieulle J, Dennetiere S, Malbranque Z, Daniel A, Bruges J, Pascal L, Brijs J, Carpentier B, Willaume A, Coiteux V, Goursaud L, Preudhomme C, Nibourel O, Duployez N. Diagnostic relevance of SH2B3 mutations in suspected myeloid malignancies and acute leukemia: insights from a large-scale NGS-based screening study. Blood Cancer J. 2025 Oct 24;15(1):176.
Podvin, B., Joudinaud, R., Roumier, C., Boudry, A., Farnault, L., Dantec, M., Berthon, C., Dumezy, F., Goursaud, L., Bucci, M., Preudhomme, C., & Duployez, N. (2025). NPM1 mutation subtype switch in acute myeloid leukemia. Haematologica. https://doi.org/10.3324/haematol.2024.286916
Sklavenitis-Pistofidis, R., Lightbody, E. D., Reidy, M., Tsuji, J., Alberge, J.-B., Aranha, M. P., Heilpern-Mallory, D., Roweth, H. G., Huynh, D., Chong, S. J. F., Chung, A. Y., Zhang, J., Hackett, L., Haradhvala, N. J., Wu, T., Su, N. K., Berrios, B., Belkin, S., Dutta, A. K., … Manier, S. (2025a). Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q+. Blood, 146(1), 89–103. https://doi.org/10.1182/blood.2024025102
Boudry A, Goursaud L, Lebon D, Dumezy F, Harrivel V, Boue-Raguet A, Joudinaud R, Marceau-Renaut A, Geffroy S, Hauspie C, Brijs J, Fenwarth L, Berthon C, Marolleau JP, Figeac M, Preudhomme C, Duployez N. Monitoring of measurable residual disease by next-generation sequencing in patients with acute myeloid leukaemia. Br J Haematol. 2025 Nov;207(5):1953-1961.
Fléchon L, Arib I, Dutta AK, Hasan Bou Issa L, Sklavenitis-Pistofidis R, Tilmont R, Stewart C, Dubois R, Poulain S, Copin MC, Javed S, Nudel M, Cavalieri D, Escure G, Gower N, Chauvet P, Gazeau N, Saade C, Thiam MB, Ouelkite-Oumouchal A, Gaggero S, Cailliau É, Faiz S, Carpentier O, Duployez N, Idziorek TB, Mortier L, Figeac M, Preudhomme C, Quesnel B, Mitra S, Morschhauser F, Getz G, Ghobrial IM, Manier S. Genomic profiling of Mycosis Fungoides identifies patients at high risk of disease progression. Blood Adv. 2024 Mar 21:bloodadvances.2023012125.
Groh M, Fenwarth L, Labro M, Boudry A, Fournier E, Wemeau M, Marceau-Renaut A, Daltro de Oliveira R, Abraham J, Barry M, Blanche P, Bodard Q, Braun T, Chebrek S, Decamp M, Durel CA, Forcade E, Gerfaud-Valentin M, Golfier C, Gourguechon C, Grardel N, Kosmider O, Martis N, Melboucy Belkhir S, Merabet F, Michon A, Moreau S, Morice C, Néel A, Nicolini FE, Pascal L, Pasquier F, Pieragostini A, Roche-Lestienne C, Rousselot P, Terriou L, Thiebaut-Bertrand A, Viallard JF, Preudhomme C, Kahn JE, Lefevre G, Duployez N; CEREO Collaborators. Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study. Am J Hematol. 2024 Jun;99(6):1108-1118.
Hasan Bou Issa L, Fléchon L, Laine W, Ouelkdite A, Gaggero S, Cozzani A, Tilmont R, Chauvet P, Gower N, Sklavenitis-Pistofidis R, Brinster C, Thuru X, Touil Y, Quesnel B, Mitra S, Ghobrial IM, Kluza J, Manier S. MYC dependency in GLS1 and NAMPT is a therapeutic vulnerability in multiple myeloma. iScience. 2024 Mar 4;27(4):109417.
Dhayer, M., Jordao, A., Dekiouk, S., Cleret, D., Germain, N., & Marchetti, P. (2024). Implementing Chicken Chorioallantoic Membrane ( CAM ) Assays for Validating Biomaterials in Tissue Engineering: Rationale and Methods. Journal of Biomedical Materials Research Part B: Applied Biomaterials, 112(11), e35496. https://doi.org/10.1002/jbm.b.35496
Hatzfeld, A.-S., Germain, N., Maboudou, P., Dhayer, M., & Marchetti, P. (2024). Medical and economic impacts of managing corneas from older donors at the tissue bank—A single-center retrospective study spanning over 12 years. Frontiers in Medicine, 11, 1415515. https://doi.org/10.3389/fmed.2024.1415515
Ingegnere, T., Segain, B., Cozzani, A., Carlsten, M., Mitra, S., & Gaggero, S. (2024). Optimizing CAR‐NK Cell Transduction and Expansion: Leveraging Cytokine Modulation for Enhanced Performance. Current Protocols, 4(11), e70040. https://doi.org/10.1002/cpz1.70040
Duployez, N., Vasseur, L., Kim, R., Largeaud, L., Passet, M., L’Haridon, A., Lemaire, P., Fenwarth, L., Geffroy, S., Helevaut, N., Celli-Lebras, K., Adès, L., Lebon, D., Berthon, C., Marceau-Renaut, A., Cheok, M., Lambert, J., Récher, C., Raffoux, E., … Preudhomme, C. (2023). UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia. Leukemia, 37(6), 1245–1253. https://doi.org/10.1038/s41375-023-01906-z
Escure, G., Fournier, E., Saade, C., Issa, L. H. B., Arib, I., Tilmont, R., Gazeau, N., Thiam, B. M., Chovet, M., Delforge, M., Gower, N., Fléchon, L., Cavalieri, D., Chauvet, P., Nudel, M., Goursaud, L., Berthon, C., Quesnel, B., Facon, T., … Manier, S. (2023). Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes. Haematologica. https://doi.org/10.3324/haematol.2023.284050
Vasseur L, Fenwarth L, Lambert J, de Botton S, Figeac M, Villenet C, Heiblig M, Dumas PY, Récher C, Berthon C, Lemasle E, Lebon D, Lambert J, Terré C, Celli-Lebras K, Dombret H, Preudhomme C, Cheok M, Itzykson R, Duployez N. LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study. Blood Adv. 2023 Aug 8;7(15):4024-4034.
Gaggero S, Martinez-Fabregas J, Cozzani A, Fyfe PK, Leprohon M, Yang J, Thomasen FE, Winkelmann H, Magnez R, Conti AG, Wilmes S, Pohler E, van Gijsel Bonnello M, Thuru X, Quesnel B, Soncin F, Piehler J, Lindorff-Larsen K, Roychoudhuri R, Moraga I, Mitra S. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein. Sci Immunol. 2022 Dec 9;7(78):eade5686.
Duployez, N., Largeaud, L., Duchmann, M., Kim, R., Rieunier, J., Lambert, J., Bidet, A., Larcher, L., Lemoine, J., Delhommeau, F., Hirsch, P., Fenwarth, L., Kosmider, O., Decroocq, J., Bouvier, A., Le Bris, Y., Ochmann, M., Santagostino, A., Adès, L., … Sébert, M. (2022). Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: An ALFA-FILO study. Blood, 140(7), 756–768. https://doi.org/10.1182/blood.2021015328
Mopin, A., Leprêtre, F., Sebda, S., Villenet, C., Ben Khoud, M., Figeac, M., Quesnel, B., & Brinster, C. (2022). Detection of residual and chemoresistant leukemic cells in an immune-competent mouse model of acute myeloid leukemia: Potential for unravelling their interactions with immunity. PLOS ONE, 17(4), e0267508. https://doi.org/10.1371/journal.pone.0267508
Shaik, F. A., Lewuillon, C., Guillemette, A., Ahmadian, B., Brinster, C., Quesnel, B., Collard, D., Touil, Y., Lemonnier, L., & Tarhan, M. C. (2022). Pairing cells of different sizes in a microfluidic device for immunological synapse monitoring. Lab on a Chip, 22(5), 908–920. https://doi.org/10.1039/d1lc01156a
Trinh, A., Khamari, R., Fovez, Q., Mahon, F.-X., Turcq, B., Bouscary, D., Maboudou, P., Joncquel, M., Coiteux, V., Germain, N., Laine, W., Dekiouk, S., Jean-Pierre, S., Maguer-Satta, V., Ghesquiere, B., Idziorek, T., Quesnel, B., Kluza, J., & Marchetti, P. (2022). Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells. Molecular Metabolism, 55, 101410. https://doi.org/10.1016/j.molmet.2021.101410
Fenwarth, L., Thomas, X., de Botton, S., Duployez, N., Bourhis, J.-H., Lesieur, A., Fortin, G., Meslin, P.-A., Yakoub-Agha, I., Sujobert, P., Dumas, P.-Y., Récher, C., Lebon, D., Berthon, C., Michallet, M., Pigneux, A., Nguyen, S., Chantepie, S., Vey, N., … Itzykson, R. (2021). A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia. Blood, 137(4), 524–532. https://doi.org/10.1182/blood.2020005524
Gazeau, N., Beauvais, D., Yakoub-Agha, I., Mitra, S., Campbell, T. B., Facon, T., & Manier, S. (2021). Effective anti-BCMA retreatment in multiple myeloma. Blood Advances, 5(15), 3016–3020. https://doi.org/10.1182/bloodadvances.2021004176
Itzykson, R., Fournier, E., Berthon, C., Röllig, C., Braun, T., Marceau-Renaut, A., Pautas, C., Nibourel, O., Lemasle, E., Micol, J.-B., Adès, L., Lebon, D., Malfuson, J.-V., Gastaud, L., Goursaud, L., Raffoux, E., Wattebled, K.-J., Rousselot, P., Thomas, X., … Duployez, N. (2021). Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy. Blood, 138(7), 507–519. https://doi.org/10.1182/blood.2021011103
Bustoros, M., Sklavenitis-Pistofidis, R., Park, J., Redd, R., Zhitomirsky, B., Dunford, A. J., Salem, K., Tai, Y.-T., Anand, S., Mouhieddine, T. H., Chavda, S. J., Boehner, C., Elagina, L., Neuse, C. J., Cha, J., Rahmat, M., Taylor-Weiner, A., Van Allen, E., Kumar, S., … Manier S*, Getz G*, Ghobrial IM* (2020). Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. Journal of Clinical Oncology, 38(21), 2380–2389. https://doi.org/10.1200/JCO.20.00437
Fournier, E., Duployez, N., Ducourneau, B., Raffoux, E., Turlure, P., Caillot, D., Thomas, X., Marceau-Renaut, A., Chantepie, S., Malfuson, J.-V., Lemasle, E., Cheok, M., Celli-Lebras, K., Guerin, E., Terré, C., Lambert, J., Pautas, C., Dombret, H., Castaigne, S., … Boissel, N. (2020). Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia. Blood, 135(8), 542–546. https://doi.org/10.1182/blood.2019003471
Martinez-Fabregas, J., Wang, L., Pohler, E., Cozzani, A., Wilmes, S., Kazemian, M., Mitra, S., & Moraga, I. (2020). CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci. Cell Reports, 33(12), 108545. https://doi.org/10.1016/j.celrep.2020.108545
Duployez, N., Marceau-Renaut, A., Villenet, C., Petit, A., Rousseau, A., Ng, S. W. K., Paquet, A., Gonzales, F., Barthélémy, A., Leprêtre, F., Pottier, N., Nelken, B., Michel, G., Baruchel, A., Bertrand, Y., Leverger, G., Lapillonne, H., Figeac, M., Dick, J. E., … Cheok, M. (2019). The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia. Leukemia, 33(2), 348–357. https://doi.org/10.1038/s41375-018-0227-5
Martinez-Fabregas, J., Wilmes, S., Wang, L., Hafer, M., Pohler, E., Lokau, J., Garbers, C., Cozzani, A., Fyfe, P. K., Piehler, J., Kazemian, M., Mitra, S., & Moraga, I. (2019). Kinetics of cytokine receptor trafficking determine signaling and functional selectivity. eLife, 8, e49314. https://doi.org/10.7554/eLife.49314
Itzykson, R., Duployez, N., Fasan, A., Decool, G., Marceau-Renaut, A., Meggendorfer, M., Jourdan, E., Petit, A., Lapillonne, H., Micol, J.-B., Cornillet-Lefebvre, P., Ifrah, N., Leverger, G., Dombret, H., Boissel, N., Haferlach, T., & Preudhomme, C. (2018). Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia. Blood, 132(2), 187–196. https://doi.org/10.1182/blood-2018-03-837781
Manier, S., Park, J., Capelletti, M., Bustoros, M., Freeman, S. S., Ha, G., Rhoades, J., Liu, C. J., Huynh, D., Reed, S. C., Gydush, G., Salem, K. Z., Rotem, D., Freymond, C., Yosef, A., Perilla-Glen, A., Garderet, L., Van Allen, E. M., Kumar, S., … Ghobrial, I. M. (2018). Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. Nature Communications, 9(1), 1691. https://doi.org/10.1038/s41467-018-04001-5
Financements
Membres
Victoria Cacheux,
PH, MD
Doriane Cavalieri
PH, MD
Christine Decanter
PH, MD
Elise Buret
IE CDD INSERM
Aya Elmesaoudi
IE CDD CHU
Emilie Laurenge
IE CDD CHU
Noémie Carlier
Tech CDD CHU
Sidonie Griffard,
Tech CDD CHU
Benjamin Segain
PhD D3
Ibtihal Hezili
PhD D2
Mélinda Dantec
PhD D1
