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U1069-N2COx

Leukemia cells are in close interaction with the bone marrow microenvironment within hypoxic leukemic niches highly involved in relapse, and N2COx is focusing its research on their role in leukemogenesis. Affiliated to the French national institute of health and medical research (INSERM) and the University of Tours, the research team (CHRU and Faculty of Medicine of Tours) deciphers the functioning of leukemia cells in the bone marrow, notably by focusing on the oxidative and energetic metabolism of the niche and its pharmaco-modulation in line with drug resistance. The team models in vitro the human bone marrow niche, more particularly by using primary mesenchymal stromal cells and by reproducing hypoxia and intra-marrow pressure. By this way, the team test and analyze the impact of new molecules on cell biology (signaling, apoptosis, cell cycle, DNA breaks, RNAseq, oxidative and energy metabolism...) and chemoresistance. 

Composed of researchers, hematologists and engineers (PhD and former post-docs), the team benefits from a very specific technical platform, including a small animal irradiator ( Faxitron®), two hypoxia and intramedullary pressure modeling stations (Avatar®), a FACS cell sorter (BD Melody®), single cell analysis systems (Chromium Controller 10X Genomics , etc ...) and real-time metabolic analyzers (Seahorse®, Omnilog®). To optimize its analytical strategies, the team has filed 3 patents and published many original methods in flow cytometry, molecular biology and metabolic analyzes.

Olivier Hérault
Prof. Olivier Hérault

Head of Entity

Contact

Email : olivier.herault@univ-tours.fr

LNOx
Faculté de Médecine de Tours, Bâtiment Dutrochet
10, boulevard Tonnellé - BP3223
37032 TOURS CEDEX 1 - France

Website

  • MDS/MPN syndromes
  • Acute Lymphoblastic Leukemia (ALL)
  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndromes (MDS)
  • Leukemia predisposition syndromes

  • Leukemia risk factors (aging - clonal hematopoiesis; environmental pollutants)
  • Metabolic specificities of the (pre-) leukemic niche. Development of original methods (quantification of reactive oxygen species, antioxidogram, infrared spectrum of plasma, energy metabolism of mesenchymal stromal cells, optical diffraction of cells, high resolution cell cycle, apoptosis)
  • Niche-related chemoresistance mechanisms (mesenchymal stromal cells). In vitro testing (CSM / hypoxia / intra-marrow pressure) and in vivo (murine mice) testing (murine models) of new molecules.

  • Targeted therapy
  • Precision medicine
  • Chemotherapy

Scientific

  • LNOx has characterized abnormalities in the oxidative/energy metabolism of leukemia cells in relation to the bone marrow microenvironment.
  • LNOx identified specific connexins (GAP junctions) on mesenchymal stromal cells of leukemic bone marrow, implicated in aracytin resistance.
  • LNOx identified epigenetic abnormalities of mesenchymal stromal cells in leukemic bone marrow iimpacting HOX genes.
  • LNOx identified the human bone marrow cytokine landscape specific to aging clonal hematopoiesis.

Medical

  • LNOx established the increased risk of AML after occupational exposure to pesticides.
  • LNOx established that 40% of subjects over 50 have ibone marrow clonal abnormalities (clonal hematopoiesis)

 

  • Ravalet N et al. Modulation of bone marrow and peripheral blood cytokine levels by age and clonal hematopoiesis in healthy individuals. Clin Immunol 2023, 255:109730
  • Roux B et al. Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia. Cancer Gene Ther 2022, 29:1263-1275
  • Gyan E et al. Adjunction of a fish oil emulsion to cytarabine and daunorubicin induction chemotherapy in high-risk AML. Sci Rep 2022, 12:9748
  • Foucault A et al. Occupational pesticide exposure increases risk of acute myeloid leukemia: a meta-analysis of case-control studies including 3,955 cases and 9,948 controls. Sci Rep 2021, 11:2007
  • Foucault A et al. Low-dose pesticides alter primary human bone marrow mesenchymal stem/stromal cells through ALDH2 inhibition. Cancers 2021, 13:5699
  • Mancini SJC et al. Deciphering tumor niches: lessons from solid and hematological malignancies. Front Immunol 2021, 12:766275
  • Guermouche H et al. High prevalence of clonal hematopoiesis in the blood and the bone marrow of healthy volunteers. Blood Adv 2020, 4:3550-3557
  • Bourgeais J, Herault O. In vitro analysis of energy metabolism in bone-marrow mesenchymal stromal cells. Methods Mol Biol 2020, 23084 (15):3550-3557
  • Vignon C et al. Involvement of GPx-3 in the reciprocal control of redox metabolism in the leukemic niche. Int J Mol Sci 2020, 21:8584
  • Vignon C et al. Reactive oxygen species levels differentiate CD34+ human progenitors based on CD38 expression. Cytometry B Clin Cytom 2020, 98:516-521
  • Picou F et al. Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes. Blood Adv 2019, 3:4271-4279
  • Kouzi F et al. Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells. Oncogene 2019, 39:1198-1212
  • Picou F et al. n-3 Polyunsaturated fatty acids induce acute myeloid leukemia cell death associated with mitochondrial glycolytic switch and Nrf2 pathway activation. Pharmacol Res 2018, 136:45-55

Research infrastructures

Microscopy

Metabolomics

Genomics

Small animal imaging

Cytometry

Platforms of the N2C (U1069) laboratory.

Irradiation

Cell culture facility

Metabolic Analysis 

Bioinformatics

Transcriptomics

Preclinical studies

Platforms of LNOx team.

 
Biological samples  

Various sources

AML

ALL

MDS

 

Collections of leukemias and myelodysplastic syndromes of the tumor bank of Tours university hospital (head: Prof. Olivier Herault).

CRB-T « Biological Resources Center - Touraine» (Scientific director: Prof. Olivier Herault).

Clinical trial

AML

ALL

MDS

 

Collection of primary cells and plasma from bone marrow and blood of patients suffering from leukemias and myelodysplastic syndromes (protocols: PLASMYC, MYLESYM, FAMYLY…).

Clinical trial

Healthy volunteers

Collection of primary cells and plasma from bone marrow and blood of healthy volunteers (HEALTHOX protocol, ClinicalTrials.gov n° NCT02789839 – Prof. Olivier Herault).

Collection of primary cells and plasma from bone marrow and blood of healthy children (MILA protocol, ClinicalTrials.gov n°NCT05792007 – Prof. Olivier Herault, Dr Julien Lejeune).
Category Models Pathology Specification Sample type Number of models Genetics characterization
In vitro Human primary cells AML - Diagnosis - -
In vitro Human primary cells AML - Relapse - -
In vitro Human primary cells Normal bone marrow - - - -
In vivo Mouse model AML FLA2, FLB1 - - -

Sources diverses

Données cliniques

 

Bases de données des protocoles dirigées par le Pr Olivier Hérault et le Pr Emmanuel Gyan (HEALTHOX, PLASMYC, MYLESYM, FAMYLY…)

Sources diverses

Données de collection d'échantillons

Données de diagnostic du microenvironnement de la moelle osseuse et données multi-omiques

 

Partnership research offers

IN VITRO EVALUATION OF THE EFFECTS OF ANTILEUKEMIC DRUGS IN A MODELED LEUKEMIC NICHE WITH OPTIMIZED BONE MARROW MICROENVIRONMENT (MSCS, HYPOXIA, PRESSURE) (MPN/ALL/AML/MDS)

METABOLIC, GENOMIC, TRANSCRIPTOMIC AND FUNCTIONAL ANALYSES OF THE LEUKEMIC NICHE FOR PHASE 1 TRIALS (MPN/ALL/AML/MDS)

Partners

Academics

Affiliation

Inserm Université de Tours