Functional evaluation of DNA methylation-controlled leukemia stem cell genes

• Applicants: Professor Miguel Andrade-Navarro, Ph.D.; Professor Dr. Frank Rosenbauer, since 9/2015
• Subject Area: Hematology, Oncology
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 171586384

DNA methylation controls cellular development and cancer growth. We have recently reported that DNA methylation represents a major epigenetic mechanism for self-renewal and lineage differentiation fate choice of hematopoietic stem cells (HSC). Our data from the current funding period of this DFG priority program revealed that DNA methylation is also important for acquisition and maintenance of leukemia stem cell (LSC) properties. We combined MLL-AF9- and Myc/Bcl2-based retroviral transduction models with a mouse strain, expressing hypomorphic levels of the main maintenance DNA methyltransferase, DNMT1, and succeeded in identifying novel methylation controlled genes potentially affecting LSC self-renewal and tumor growth. For the upcoming period of this priority program, we propose to further investigate the functions and mechanisms of action of these genes, in particular under in vivo conditions. Moreover, we will study their involvement in human leukemia. Finally, we will analyze the epigenome and transcriptome of a conditional DNMT1 knockdown AML mouse model, with the aim to genetically mimic, and thus better understand, downstream effects of demethylating agents on growth of established tumors.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1463: Epigenetic Regulation of Normal Hematopoiesis and its Dysregulation in Myeloid Neoplasia
• Participating Persons: Professor Dr. Christian Buske; Professor Dr. Carsten Müller-Tidow; Professor Dr. Michael Rehli
• Ehemalige Antragstellerin: Irina Savelyeva, Ph.D., until 9/2015