Project Details
Projekt
Identification of clinically relevant epigenomic events in pediatric acute lymphoblastic leukemia
Subject Area
Pediatric and Adolescent Medicine
Bioinformatics and Theoretical Biology
Bioinformatics and Theoretical Biology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 418080850
Lymphoblastic leukemias are among the most common neoplastic diseases in children constituting around 30% of cancers before the age of 15 years. While current treatments have improved the long-term survival of many patients, children with specific genomic alterations such as hypoploidy or translocations affecting the epigenomic modifier KMT2A face a dire prognosis. Even intensified therapy regimes such as stem cell transplantations do not substantially improve the outcome in these cases. The molecular mechanisms of childhood leukemias are not sufficiently understood, therefore the efforts in research and drug development have stagnated in the last years. Meanwhile, it has become evident that epigenomic alterations play an important role in leukemogenesis and in the development of resistances to therapeutic agents. This is dramatically true for pediatric leukemias with especially poor prognosis, including Philadelphia chromosome (Ph)/BCR/ABL1-positive acute lymphoblastic leukemia and leukemias with KMT2A rearrangement. While the latter, a histone methyltransferase, is a direct modifier of the epigenetic code, also the BCR-ABL1 fusion gene has been shown to substantially impact the epigenome. Thus, the analysis of the epigenome will not only allow us to better understand the pathobiology of the disease, moreover it will enable us to identify new prognostic markers, as well as to identify the clinical needed potential novel therapeutic targets. A thorough and complete epigenomic investigation of these childhood cancers with high clinical relevance is still withstanding. In this project we aim to completely characterize the epigenomes of BCR/ABL1 and KMT2A positive cancers with histone ChIP-Seqs, reduced representation and whole genome bisulfite sequencing, ATAC-Seq, RNA-Seq as well as single cell RNA-Sequencing. The comprehensive data set generated within this project will extend the knowledge about the molecular mechanisms of childhood leukemia and allow to understand the specificities of these cancers as compared to leukemias of adults for which similar data sets have already been successfully collected and published.
DFG Programme
Research Grants
International Connection
Netherlands, Spain
Co-Investigators
Professorin Dr. Claudia Baldus; Professor Dr. Gunnar Cario; Dr. Helene Kretzmer
