The molecular pathology of myelodysplastic syndromes

Myelodysplastic syndrome (MDS) is one of the most frequent bone marrow malignancies, affecting around 1,500 Canadians every year. It is characterized by anemia and a high risk of transformation to acute myeloid leukemia (AML). The only curative option is bone marrow transplantation, which carries high mortality and morbidity. Other standard treatment modalities such as lenalidomide and 5-azacytidine are characterized by a short response and a high degree of relapse. The molecular causes of treatment resistance and disease transformation in this situation are not fully understood. Dr. Martin Jadersten aims to investigate the genetic changes associated with initiation of MDS and understand how these changes contribute to subsequent therapy failure or disease progression. He will investigate serial samples from 10 MDS patients before and after leukemic transformation. RNA and DNA will be extracted from bone marrow cells and marrow fibroblasts (non-malignant control cells), and global genetic investigations such as exome (DNA), transcriptome (RNA) and micro RNA (regulatory RNA) sequencing will be conducted. Powerful bioinformatics methods will be used to analyze the data and identify genomic alterations, including gene fusions, DNA insertions/deletions, and alternative expressions of genes (isoforms). These identified genetic alterations will be validated for recurrence in a large group of MDS patients, and candidate genes will be tested functionally with cell line experiments and mouse models. Dr. Jadersten's work is already well underway. He has processed three samples from one MDS patient with all of the methods above and has shown that there are significant changes in micro-RNA expression between these time points. As the disease has progressed in this patient, a number of alternatively expressed genes appear, which potentially indicates alterations in the RNA-splicing machinery. By the time the patient develops AML, there is almost a complete loss of two clusters of important regulatory genes involved in embryogenesis and cancer. As this patient sequentially received the only two registered drugs for MDS (lenalidomide and 5-azacytidine), Dr. Jadersten will attempt to determine potential resistance mechanisms using the data already obtained. Identification of key mediators of disease development, leukemic transformation and drug resistance may sharpen our prognostic tools, improve clinical management and provide a basis for development of targeted therapy.