Présentation
À propos
Leïla Chrétien, PhD, CRHC, is a Senior Research Scientist at INSERM and Principal Investigator of the Mastocytosis Program within the Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications at Institut Imagine. She also serves as Scientific Referent within CEREMAST, the French National Reference Center for Mastocytosis.
Her research focuses on mastocytosis, a rare and heterogeneous group of disorders characterized by the abnormal accumulation of neoplastic mast cells. Although the activating KIT D816V mutation is present in the majority of patients, it does not fully explain disease heterogeneity or resistance to targeted therapies. In close collaboration with CEREMAST and clinicians at Necker Hospital, her group investigates the molecular mechanisms cooperating with KIT in disease initiation, progression and therapeutic resistance, with the aim of identifying novel biomarkers and therapeutic targets. Her research combines patient-based studies, molecular and genomic approaches, functional validation and preclinical models, with a strong focus on translational research.
She has extensive experience in hematopoiesis and hematological malignancies and has contributed to the identification and functional characterization of novel molecular mechanisms involved in hematopoietic tumorigenesis. She also developed expertise in pluripotent stem cell (iPSC)-based disease modeling and personalized cell therapy strategies during an INSERM–Harvard Medical School interface fellowship. She currently serves on the boards of the French Society for Cellular and Gene Therapy (SFTCG) and the French Society for Stem Cell Research (FSSCR), and is a member of the INSERM CSS2 scientific committee.
Projet scientifique
Our studies identified cooperating pathways involved in mast cell transformation and disease progression, including Hedgehog signaling and mechanisms linking KIT mutations to telomere biology and cellular senescence. We showed that aberrant Hedgehog signaling cooperates with oncogenic KIT to promote neoplastic mast cell proliferation and disease progression, identifying a potential therapeutic vulnerability. We also demonstrated that non-PTD KIT mutations in childhood mastocytosis are associated with telomere shortening and cellular senescence through increased p38 MAPK activation and reduced TRF2 occupancy, providing a mechanistic explanation for the spontaneous regression of childhood disease.
A major recent project identified the receptor tyrosine kinase AXL, broadly implicated in cancer progression, tumor cell survival and resistance to targeted therapies, as a previously unrecognized regulator of neoplastic mast cells. Our findings indicate that inflammatory interferons induce AXL expression and that AXL promotes mast cell proliferation, survival and resistance to KIT-targeted therapy. In a translational cohort spanning the clinical spectrum of mastocytosis, soluble AXL emerged as a promising biomarker of advanced disease. This work is currently being prepared for resubmission to a peer-reviewed journal.
In parallel, ongoing projects investigate the contribution of apoptotic pathways to disease progression and therapeutic resistance, with a particular focus on BCL2 and FAS/FASLG. Our findings indicate that persistent BCL2 activity may contribute to resistance to KIT-targeted therapy and provide a rationale for combined therapeutic approaches. This work has contributed to the development of a clinical trial combining a KIT inhibitor with a BCL2 inhibitor, which is currently ongoing in patients with advanced mastocytosis. More recently, we identified germline mutations in the FAS and FASLG genes in a subset of patients with mastocytosis. On the other hand, in patients without FAS/FASLG mutations, we observed reduced FAS expression in advanced compared with indolent systemic mastocytosis. FAS is the principal genetic driver of autoimmune lymphoproliferative syndrome (ALPS) and a central regulator of extrinsic apoptosis. Its dysfunction is implicated in tumor cell survival and immune escape in several cancers. Our ongoing studies aim to define the molecular mechanisms underlying FAS dysfunction and determine whether defective FAS-mediated apoptosis contributes to the persistence and progression of neoplastic mast cells.
Together, these projects aim to identify complementary molecular vulnerabilities and translate these discoveries into clinically relevant biomarkers and precision therapeutic strategies for patients with mastocytosis.
Among her publications:
Telomere occupancy by TRF2 is altered by KIT mutations and correlates with mastocytosis regression. Julie Bruneau, Sophie Georgin-Lavialle, Sophia Ladraa, Zakia Belaid, Isabelle Plo, Sébastien Letard, Erinn Soucie, Irena Draskovic, Nicolas Goudin, Marie Bouillié, Yves Lepelletier, Julien Rossignol, Laura Polivka, Laurent Frenzel, Olivier Lortholary, Sylvie Fraitag, Christine Bodemer, Patrick Revy, Michel Arock, Thierry-Jo Molina, Arturo Londono-Vallejo, Patrice Dubreuil, Leila Maouche-Chretien*, Olivier Hermine*. Blood Cancer J 2025 Nov 5; PMID: 41193460.
AXL mediates mast cell survival and resistance to tyrosine kinase inhibitors in mastocytosis. Kitsada Kangboonruang; Philippe Drabent; Fatlinda Maksut; Maxime Heintzé; Yves Lepelletier; Ludovick Lhermitte; Mélanie Feroul; Sébastien Letard; Fabienne Brenet ; Cécile Méni, Nicolas Cagnard, Vincent Bondet, Guillaume Lefèvre, Julie Bruneau, Michael Dussiot, Héloïse Halse, Amélie Bigorgne, Anne-Florence Collange, Hassiba Bouktit, Frédérique Rétornaz, Jérome Megret, Stéphane Barete, Nathalie Droin, Cristina Bulai Livideanu, Angélique Lebouvier, Darragh Duffy, Eric Solary, Michel Arock, Damaj Gandhi, Christine Bodemer, Julien Rossignol, Laura Polivka, Thierry Molina, Olivier Hermine, Leila Maouche-Chretien. doi: 10.1101/2025.11.03.686205.
Successful Derivation of Hepatoblasts, Cholangiocytes and Hepatocytes from Simian Induced Pluripotent Stem Cells. Eleanor Luce; Clara Steichen; Soumeya Abed; Anne Weber; Philippe Leboulch; Leila Maouche-Chrétien*; Anne Dubart-Kupperschmitt* : . International Journal of Molecular Sciences . 2022-09-17. DOI: 10.3390/ijms231810861
Successful Derivation of Hepatoblasts, Cholangiocytes and Hepatocytes from Simian Induced Pluripotent Stem Cells. Aurelie Mouka, Brahim Arkoun...Gérard Tachdjian, Leïla Maouche‐Chrétien* and Lucie Tosca* : x Scientific Reports , August 2022. DOI: 10.1038/s41598-022-17337-2
The association of Greig syndrome and mastocytosis reveals the involvement of the hedgehog pathway in advanced mastocytosis. L. Polivka, V. Parietti, E. Soucie, E. Bayard, R. Rignault, D. Canioni, S. Fraitag, L. Lhermitte, M. Feroul, M. Tissandier, J. Rossignol, L. Frenzel, N. Cagnard, C. Meni, H. Bouktit, AF. Collange, C. Gougoula, M. Parisot, B. Bader-Meunier, M. Arock, S. Hadj-Rabia, U. Rüther, P. Dubreuil, C. Bodemer, O Hermine, L Maouche-Chretien* : . Blood. 2021 Dec. PMID: 34424959 .
Parallel assessment of globin lentiviral transfer in iPS and somatic hematopoietic stem cells from the same transplanted human β-thalassemia patient. Abed S, Tubsuwan A, Chaichompoo P, Park IH, Benyoucef A, Tosca L, Fucharoen S, Daley GQ, Payen E, Chrétien S, Leboulch P, Maouche-Chretien L.: Transplantation of Macaca cynomolgus iPS-derived hematopoietic cells in NSG immunodeficient mice. Haematologica. 2015 . PMID: 26088930• Tubsuwan A., Abed S., Deichmann A., Bartholomä C, Kadri Z., Fucharoen S., von Kalle C.,Schmidt M., Eaves C.J., Leboulch P, Maouche-ChrétienL : Stem cells, 2013. PMID: 23712774
Financements
