Elizabeth Macintyre, M.D-PhD FRCP/Path is Professor of Hematology at the Paris Descartes Medical School. She trained in internal Medicine and clinical and laboratory Hematology in the UK (Newcastle and UCL), did her PhD in Paris (St. Louis) and her post-doctoral fellowship in Harvard. She joined the Medical Faculty at Descartes in 1992 and has headed the Hematology Laboratory and the integrated Hematopathology Cancer programmes since 1999 and 2007, respectively.

Vahid Asnafi, M.D-PhD studied Medicine at Paris Descartes before specializing in laboratory Hematology. He obtained his PhD at Descartes in 2003 before doing his post-doctoral studies with Pierre Ferrier at CIML, Marseille. Returning to Necker in 2005, he was appointed full Professor of Hematology in 2012 and now heads the Onco-Hématology laboratory and well as co-directing the "Normal and Pathological Lymphoid Differentiation Team" at INEM

Focus

We study molecular mechanisms controlling TCR VDJ rearrangements during human T-cell ontogeny and their implication in (epi)genetic deregulation in T-lymphoid oncogenesis, in order to develop targeted therapeutics for leukemia and lymphoma.

Introduction

Our research essentially involves analysis of the mechanisms controlling human T lymphoid ontogeny and oncogenic transformation in immature T lymphoid malignancies, particularly T-cell lymphoblastic acute leukemias (T-ALL) and lymphomas (T-LBL).

T-ALLs are malignant clonal proliferations arrested at specific stages of thymic differentiation. Oncogenic deregulation and physiological T lymphopoiesis, including the mechanisms regulating the somatic rearrangements leading to assembly of a T Cell Receptor (TCR), are intimately linked, which implies the contribution of physiological proliferative/apoptotic signals to the oncogenic process.

We have developed cellular and molecular characterisation of lymphoid malignancies in close collaboration with clinical cooperative and fundamental cognitive research groups in order to ensure optimal human tissue resource management and valorisation. All research projects are based on the principal that unravelling oncogenic pathways with an aim to improving treatment requires in-depth understanding of normal development of the system which has undergone deregulated tissue homeostasis.

These studies are possible due to close collaboration with the adult (Group for Research in Adult ALL or GRAALL and Lymphoma Study Association or LYSA) and pediatric (Société Française des Cancers de l’Enfant or SFCE Leukemia and Lymphoma committees) clinical cooperative groups, and with a variety of European networks, such as the EuroFLOW, EuroMRD, EuroClonality and Blueprint consortia.

Research objectives

Cellular and molecular characterization of lymphoid malignancies, with particular emphasis on T lymphoid oncogenesis:

1. Read the language of antigen receptor (Immunoglobulin and T Cell Receptor) rearrangements in order to:
   • understand maturation arrest and lineage affiliation in order to improve classification of lymphoid malignancies
   • explore the potential oncogenic role of deregulated receptor rearrangements in the development of lymphoid malignancies
   • analyse TCR signalling function in T lymphoid oncogenesis
   • identify the potential for therapeutic correction of blocked lymphoid maturation secondary to deregulated receptor rearrangement
   • explore the mechanisms of action of Homeotic proteins during normal and pathological thymopoiesis
   • Explore the epigenetic regulation of human VDJ rearrangements during T lymphoid development (Blueprint)
2. Explore Immature T/My/NK/ILC disorders in order to explore the interface between the lymphoid and myeloid lineages
3. Study the Role of cytokine receptors, NOTCH1/FBXW7 pathway deregulation and aberrant signalling pathways in T-lymphoid oncogenesis
4. Use innovative cellular and molecular techniques in order to improve integrated management of patients with leukaemia and lymphoma at diagnosis and follow-up, with particular emphasis on:
   • Ig/TCR markers for minimal residual disease personalized management in ALL and NHL
   • Multiparameter flow cytometry
   • Digital droplet quantification
   • High-throughput somatic onco- and immuno-genetics at diagnosis and follow-up

5 main publications

• Trinquand A et al. (2016) Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia. Cancer Discov. Sep;6(9):972-85
• Malcolm et al. (2016) NPM-ALK mimics thymic pre-TCR expansion requiring transient TCR expression for thymic egress and peripheral ALCL Nature Communications. 7:10087
• Cieslak A et al. (2014) RUNX1 dependent RAG1 deposition instigates Human TCRα locus rearrangement. J Exp Med. Aug 25;211(9):1821-32
• Trinquand A. et al. (2013) Towards a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-ALL: a GRAALL Study. Journal of clinical oncology Dec 1;31(34):4333-42
• Dadi S et al. TLX homeodomain oncogenes mediate T-cell maturation arrest in T-ALL via interaction with ETS1 and suppression of TCRα gene expression. Cancer Cell. Apr 17;21(4):563-76

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