Identification of new clinically significant genetic and epigenetic changes using next-generation high-throughput sequencing in patients with chronic myeloid leukemia with an unfavorable course of the disease

Chronic myeloid leukemia (CML) is a model cancer that has been studied for many years, but the genetic changes responsible for disease progression are poorly understood. The main goal of the project is to detect aberrations in the genome and epigenome of CSF responsible for the unfavorable course of the disease, i.e. resistance to targeted therapy and / or progression to the acute phase, using high-throughput techniques. The next goal is to investigate the potential biological role of the aberrations found and to attempt experimental blocking in in vitro models. In the proposed project, the search for new genetic and epigenetic aberrations in CSF will be performed using the technology of enriching DNA libraries with specific sequences (exomal and CpG islands) and then high-throughput sequencing. In the next stage, the biological role of selected aberrations in disease progression and drug resistance (including gene silencing, directional mutagenesis) and an attempt to experimentally block the detected targets with the use of computer modeling and aptamer synthesis will be examined on the in vitro models of CMF. Despite the increasing use of high-throughput sequencing, many cancers remain poorly characterized, as exemplified by chronic myeloid leukemia, especially in terms of lesions responsible for disease progression. Understanding new genetic and epigenetic changes in CML and examining their biological significance in cellular models may contribute to a better understanding of the pathogenesis of CML. and to develop new and better therapies for adversely affected patients, as well as therapies which, by hitting cancer stem cells, will give a chance for a complete cure. The implementation of the HARMONIA grant would enable not only the continuation but a significant extension of the long-term cooperation between the project manager (Dr. T. Stokłosa) and the foreign partner (Dr. T. Skórski). A team of contractors including scientists (geneticists, biotechnologists and bioinformatics) and clinicians and a modern workshop for genetic research (NGS platform) recently available at the Medical University of Warsaw, on the one hand, and on the other hand, the possibility of translational research on in vitro models, including computer modeling and synthesis of new molecules with a foreign partner and its vast experience and expertise in research on the molecular pathogenesis of leukemias give a real chance to make important discoveries. The HARMONIA grant would provide a unique opportunity to obtain synergy between the research carried out by both partners. This could contribute to a better understanding of the pathogenesis of CML and in the future, hope for better therapy for the sick. In the long term, the results obtained in the implementation of the grant could constitute an introduction to further translational research on in vivo models. An additional benefit would be short scientific internships for the implementation of research tasks by young team members at a foreign partner's, which would contribute to the exchange of experiences and research methods.