Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells.

Abstract 735

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies that are characterized by ineffective hematopoiesis resulting in peripheral cytopenias and a hypercellular bone marrow. In order to gain insight into the molecular pathogenesis of the MDS, we have determined the transcriptome of the hematopoietic stem cells (HSC) of 183 MDS patients and 17 healthy controls. The CD34⁺ cells obtained from MDS patients and healthy individuals were analyzed using Affymetrix U133 Plus2.0 arrays. Global pathway analysis using the Ingenuity software and the DAVID database has identified critical deregulated gene pathways and gene ontology (functional) groups perturbed in MDS HSC compared with normal HSC. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathway. Moreover, we have identified multiple pathways that are deregulated in specific MDS karyotypic groups and between early (subtype RA) and advanced MDS (subtype RAEB2). Among the most significantly deregulated gene pathways and ontology groups in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of the cell cycle, DNA damage response and checkpoint pathways. The clinical behavior of patients with del(5q), +8 or–7/del(7q) is different and we have identified distinct gene expression profiles and deregulated gene pathways for MDS defined by these major karyotypic groups. The most significantly deregulated gene pathways in del(5q) MDS include primary immunodeficiency signaling, Wnt/beta-catenin signaling, integrin signaling, cell cycle regulation and Huntington's disease signaling. Patients with the 5q- syndrome also show deregulation of the p53 pathway. Moreover, chromatin assembly and translation are among the most significant gene ontology groups in del(5q) MDS. We have found that MDS with the–7/del(7q) is characterized by deregulation of multiple pathways involved in cell survival, differentiation, apoptosis and growth, and include SAPK/JNK, NF-kB, PI3K/AKT and ceramide signaling pathways. Strikingly, all of the most significantly deregulated gene pathways in trisomy 8 MDS in our study concern or are associated with the immune response, and include B-cell receptor signaling, antigen presentation and CTLA4 signaling in Cytotoxic T lymphocytes pathways. These data are consistent with an immune system role in the pathogenesis of MDS with trisomy 8. Importantly, much of the deregulated pathway data generated in this study is in accord with the known biology of MDS. On the basis of our observations, we suggest a model for MDS in which immune deregulation and activation of apoptosis pathways in early MDS cells, consistent with clinically observed ineffective hematopoiesis, functions as a barrier to prevent leukemic transformation. Disruption of the DNA damage check points in advanced MDS results in an increase in the error rate of DNA repair with a concomitant increase in genomic instability, leading to evolution to AML. This is the first study to determine deregulated gene pathways and ontology groups in the HSC compartment of a large group of patients with MDS. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype, provide important new insights into the molecular pathogenesis of this disorder, and may represent new targets for therapeutic intervention.