GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

• Published in: Journal of hematology and oncology 2016-01, Vol.9 (5), p.5-5, Article 5
• Main Authors: Guerenne, Laura, Beurlet, Stéphanie, Said, Mohamed, Gorombei, Petra, Le Pogam, Carole, Guidez, Fabien, de la Grange, Pierre, Omidvar, Nader, Vanneaux, Valérie, Mills, Ken, Mufti, Ghulam J, Sarda-Mantel, Laure, Noguera, Maria Elena, Pla, Marika, Fenaux, Pierre, Padua, Rose Ann, Chomienne, Christine, Krief, Patricia
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Disease Models, Animal; Gene expression; Gene expression profile; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Genetic aspects; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Life Sciences; MDS; Mice; Mice models; Mice, Transgenic; Myelodysplastic syndrome; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Oligonucleotide Array Sequence Analysis - methods; Physiological aspects; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Signal Transduction - genetics
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-016-0235-8

In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.