Project Details
Projekt
Targeting Transcriptional Addiction in Acute Myeloid Leukemia with KMT2A Partial Tandem Duplication
Applicant
Dr. Julian Ronnacker
Subject Area
Hematology, Oncology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 568893482
Introduction: Acute myeloid leukemia (AML) remains a fatal disease despite intensive research and the use of targeted therapies. This is particularly true for older patients, as established AML therapies such as intensive chemotherapy or stem cell transplantation are associated with high toxicities. In addition to epigenetic changes, transcriptional addiction plays a decisive role in the pathogenesis of AML, as leukemia cells are dependent on a limited number of dysregulated transcription programs. In AML subtypes with partial tandem duplication of the KMT2A gene (KMT2A-PTD), overexpression of the oncogenic target genes HOXA9 and MEIS1, which contribute significantly to leukemogenesis, is observed. Objective: The aim of the project is to decipher the transcriptional mechanisms that lead to the activation of HOXA9 and MEIS1 in AML with KMT2A-PTD. By identifying the underlying transcriptional dependencies, new therapeutic targets will be defined. Methodological approach: In the first part of the project, established AML cell lines are used that already carry the KMT2A-PTD. In these cell lines, HOXA9 and MEIS1 will be labeled by fluorescent reporters (mNeongreen) using CRISPR /Cas9 technology. In the second part of the project, these reporter cell lines will be used for genome-wide CRISPR/Cas9 screens (to knock out certain key genes) and chemical/drug-based screening methods. By decreasing mNeongreen expression, determined by fluorescence measurement, critical signaling pathways and genes responsible for the activation of leukemogenic genes can be identified. In addition, pharmacological approaches will be tested to evaluate the effect of potential inhibitors on the transcription programs. The final stage of the project involves the validation of the identified target structures. Genetic manipulations and pharmacological interventions will be carried out in vitro and in vivo on AML models. The data obtained will provide information on the extent to which influencing transcriptional dependence leads to a reduction in leukemia cell growth and whether these approaches have the potential to be pursued in future clinical trials. Expected results and relevance: The project aims to gain new insights into the mechanisms of transcriptional addiction in AML and thus develop innovative therapeutic approaches. The results could not only improve the treatment of AML with KMT2A-PTD, but also have a broader impact on AML subtypes that depend on HOX and TALE genes. Overall, this will make an important contribution to the development of new targeted AML therapies.
DFG Programme
WBP Fellowship
International Connection
United Kingdom
