Project Details
Projekt
Targeting the non-coding stem cell signature in childhood acute myeloid leukemia
Subject Area
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282
Despite increased research on the plethora of transcripts that arise from non-protein-coding regions of the genome, our knowledge of non-coding RNAs is still far from being applied in a clinical context. This shortfall is particularly relevant to pediatric acute myeloid leukemia (AML), the treatment of which has hardly improved in three decades, and for which targeted strategies stand to greatly ameliorate long-term treatment-related toxicities and quality of life for young patients. Understanding noncoding RNA (ncRNA)-mediated mechanisms of stem cell maintenance and how these processes are hijacked during malignant transformation is crucial for understanding the pathogenesis of leukemia, and will lay a foundation for developing novel targeted cancer-specific therapies that eradicate self-renewing leukemic stem cells.We recently built a comprehensive resource defining the ncRNA landscape of the human hematopoietic system (www.lncScape.de)1 and identified a core ncRNA stem cell signature shared by normal hematopoietic stem cells (HSCs) and pediatric leukemia blasts. Since long non-coding RNAs (lncRNAs) have been shown to regulate epigenetic and transcriptional pathways, we hypothesize that lncRNAs from the core stem cell signature shape the cellular chromatin and transcriptional landscape and thereby coordinate self-renewal, proliferation and differentiation in normal and malignant stem cells. To identify functionally relevant stem cell-specific lncRNAs within this signature, we applied two complementary CRISPRi-based screening strategies in vitro and in vivo. Knockdown of 17 lncRNA genes efficiently and significantly perturbed leukemic growth in two or more cellular contexts. In this project we will therefore (1) characterize 5 high confidence stem cell-specific lncRNAs that are essential for leukemia progression and (2) resolve their functional and mechanistic features. We will additionally (3) evaluate pre-clinical RNA-centered therapeutic interventions, with the aim of overcoming current obstacles in the treatment of pediatric AML. Targeting this malignancy at its core could lead to a paradigm shift in cancer treatment – shifting the focus to the underlying genetic programs that induce and sustain cancer, rather than the oncogenic hit itself.
DFG Programme
Research Units
