LEILA MAOUCHE CHRETIEN
  • E-mail :[email]
  • Phone : +33 688809846
  • Location : PARIS, France
Last update 2022-01-07 11:13:04.792

LEILA MAOUCHE CHRETIEN Hematopoiesis, oncogenesis and therapies

Course and current status

Since 2016  

Group leader (CRCN-INSERM); Imagine institute, Paris

Topic: Mastocytosis disease and Stem cells.

Multi-thematic team leader: Pr Olivier Hermine

Director of the institute: Pr Stanislas Lyonnet

 

2008-2016    

Group leader - iMETI/STI-UMR-E 007. CEA Fontenay-aux Roses

Topic: Disease modeling, iPS cell-based therapy and Gene therapy. 

 Director: Pr Philippe Leboulch.

 

2006-2008       

PI of a research project. Cochin Hospital, Paris

Topic: Embryonic and adult hematopoietic stem cells

Director: Pr Pierre-Olivier Couraud

 

2004-2006     

Scientist at Harvard Medical School. Boston 

Division of Pediatric Hematology/Oncology, Children's Hospital, Harvard Stem Cell Institute

Topic: Embryonic stem cells and hematopoietic tissue engineering.

Director : Pr George Q. Daley

 

2000-2004     

PI of a research project. Cochin Hospital, Paris

Topic: Adult stem cells and Leukemia 

Director: Pr Axel Khan.

 

1994-2000      

Postdoctoral fellow and Junior scientist (CR2). Henri Mondor hospital, Créteil

Topic: Hematopoiesis, erythropoiesis and leukemia.

Director : Dr PH Roméo.

 

1990-1994       

PhD program: EFS, Paris

Topic: Epo-R gene cloning and regulation in erythropoiesis.

Scientific summary

My scientific career has been devoted to unraveling the underlying mechanisms that regulate different lineages of normal and leukemic hematopoiesis and developing innovative therapeutic strategies. I dedicated my PhD to Epo receptor gene cloning and its regulation in erythropoiesis (1-2-3). During my postdoctoral fellowship in Paul Henri Roméo's laboratory where I was recruited as CR2 INSERM, I developed molecular innovative approaches that led us to clone the first SCL/TAL1 target gene in red cells and to discover its binding to DNA via a multi-factorial complex (4). SCL is essential for hematopooiesis, erythropoiesis but also involved in 40% of childhood T-cell acute lymphoblastic leukemia (ALL-Ts). To assess its role in the development of ALL-Ts, I used a mouse animal model and demonstrated its inability, alone, to induce ALL-Ts, unlike thought initially (5). As I was actively involved in setting up the molecular biology lab of the anathomopathology service at Mondor, we compared samples from patients with B cell lymphoma using a DDRT technique; we cloned a new gene and identified a new prognostic marker involved in diffuse large B cell lymphoma (LDGCB) and Mediastinal B-Lymphoma, respectively (6-7).

In 2004, I was awarded an INSERM/HARVARD Medical School interface contract and joined an excellent laboratory on hematopoiesis, embryonic stem cells (hESCs-mESCs) headed by George Daley (Division of Pediatric Hematology/Oncology, Children's Hospital, Harvard Stem Cell Institute). I participated to a great work showing the involvement of Wnt3A and CDX-HOX in the generation of hematopoietic stem cells (HSCs) during the very early stage of mESC differenciation (8). A collaboration with S. Orkin allowed to show that the ubiquitously expressed Timp-1 gene is activated in red cells in response to Epo and is regulated by GATA-1 factor (9).

The discovery of iPSC was published after my return to France. Having acquired excellent skills in hESCs and hematopoietic tissue engineering, I joined the “Innovative Therapies” Department headed by Philippe Leboulch and set up a regenerative cell therapy group. The synergy with the host team, expert  in gene therapy, thalassemia and erythropoiesis perfectly suited my expectations. For therapeutic purposes, I assessed the potential of iPSCs to produce hematopoietic cells and evaluated their capacity of reconstitution in vivo (10). As I participated to the first successful clinical trial of gene therapy for beta-thalassemia carried out by P. Leboulch (11), I derived patient’s thalassemia iPSC and developed several international collaborations to compare gene therapy and regenerative therapy for the treatment of beta – thalassemia, in NSG mice (12).

My expertise in iPSCs has attracted teams working on non-hematopoietic diseases such as Gerard Tachdjian's team at Beclère hospital, to study the causes of infertility (13, and under review), and Anne-Dubart's team at Paul Brousse hospital, to carry out liver regeneration for therapeutic purposes (submitted).

Even though my experience at the CEA was excellent, I was keen to move closer to the hospital and patients to conduct more translational research; in 2016, I moved to IMAGINE to lead a group on mastocytosis in the multi-thematic team of Olivier Hermine, head of the hematology service. My work on iPSC is still ongoing but at a less frenetic rate.  In my group, we are mainly interested in mastocytosis, searching for new genes involved in the development of this rare hematopoietic disease to identify new therapeutic targets.

While focusing on familial cases, we have recently demonstrated, for the first time, that inherited mutations deregulating hedgehog (Hh) signaling pathway synergizes with KIT pathway to induce mastocytosis. A combination of tyrosine kinase inhibitors (TKi) and Hh inhibitors (Hhi) improved the survival of mice with aggressive mastocytosis (14). This result supports the total or partial ineffectiveness of TKi usually used to block the constitutively activated KIT receptor in patients with aggressive mastocytosis. Analysis of new patients uncovered novel inherited mutations in FAS and AXL genes. Both genes have never been studied in mastocytosis and are good candidates to explain the resistance of neoplastic mast cell to death.  We aim now to decipher their contribution in mastocytosis development, in collaboration with different teams in and outside IMAGINE/Necker, in order to develop new multidrug and personalized therapeutic strategies.

For my publications, better to use ORCID as pubmed is not complete due to the use of different names

https://orcid.org/0000-0001-5747-9719

maouche l[Author]
maouche chretien l[Author]

Main publications

  1. PMID: 1668607
  2. PMID: 8127671  
  3. PMID: 8521844 
  4. PMID: 9724651  
  5. PMID: 12091340
  6. PMID: 9771967
  7. PMID: 10552968
  8. PMID: 18371423
  9. PMID: 16107690
  10. PMID: 26088930
  11. PMID: 20844535
  12. PMID: 23712774
  13. PMID: 28045072
  14. PMID: 34424959

{page:WordSection1;}ol {margin-bottom:0cm;}ul {margin-bottom:0cm;}

Image d’exemple