Oncotarget

Research Papers:

Molecular dissection of engraftment in a xenograft model of myelodysplastic syndromes

Mathieu Meunier _, Charles Dussiau, Natacha Mauz, Anne Sophie Alary, Christine Lefebvre, Gautier Szymanski, Mylène Pezet, Françoise Blanquet, Olivier Kosmider and Sophie Park

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Oncotarget. 2018; 9:14993-15000. https://doi.org/10.18632/oncotarget.24538

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Abstract

Mathieu Meunier1,2,*, Charles Dussiau3,*, Natacha Mauz1,2, Anne Sophie Alary3, Christine Lefebvre4, Gautier Szymanski4, Mylène Pezet5, Françoise Blanquet6, Olivier Kosmider3 and Sophie Park1,2

1University Clinic of Hematology, CHU Grenoble Alpes, Grenoble, France

2TIMC-Therex, UMR 5525 CNRS, Grenoble Alpes University, Grenoble, France

3Hématologie Biologique, Hôpital Cochin, Assistance Publique-Hôpitaux De Paris, Paris, France

4Laboratory of Hematology, Onco-Genetic and Immunology, Biology and Pathology Institute, Grenoble, France

5Optical Microscopy and Flow cytometry Core, Institute for Advanced Biosciences, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France

6Plate-Forme De Haute Technologie Animale, UMR5525, Grenoble Alpes University, Grenoble, France

*These authors have contributed equally to this work

Correspondence to:

Mathieu Meunier, email: mmeunier2@chu-grenoble.fr

Keywords: myelodysplastic syndrome; patient derived xenograft; bone marrow microenvironment; mesenchymal stromal cells; mutational hierarchy

Received: October 19, 2017     Accepted: February 01, 2018     Epub: February 20, 2018     Published: March 13, 2018

ABSTRACT

Myelodysplastic syndromes (MDS) are oligoclonal disorders of the hematopoietic stem cells (HSC). Recurrent gene mutations are involved in the MDS physiopathology along with the medullar microenvironment. To better study the heterogeneity of MDS, it is necessary to create patient derived xenograft (PDX).

We have reproduced a PDX model by xenografting HSC (CD34+) and mesenchymal stromal cells (MSC) in NOD/SCID/IL2rγ-/- mice with primary samples from one RAEB2, two RAEB1 and one RARS patients harboring karyotype abnormalities and gene mutations. The average human chimerisms ranged from 59.7% to 0.0175% for the 4 patients. Secondary grafts (G2) were only performed for mice derived from the RAEB2 patient and the average human chimerism was 53.33%. G1 mice 1 and 2, and their derived G2 mice showed less than 20% of medullar blasts whereas mouse 3 and the resulting G2 mice transformed to AML. Clonal architecture was dissected in the different hematopoietic progenitors (HP) harvested from G1 and G2 mice. By direct Sanger sequencing, we found the 4 initial mutations in each HP subpopulation and those mutations had the same variant allele frequency in the CD34+ CD38- HSC from G1 and G2 mice by next generation sequencing (NGS). Targeted NGS analysis done in HSC of mouse 3 did not show any additional driver gene mutations explaining the transformation to AML.

To conclude, we have generated a PDX mouse model that perfectly reproduces the MDS founder clone which is stable over time, allowing us to consider this system as a powerful tool to test therapeutic approaches.


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