Project description DEENESFRITPL Novel route to preventing acute myeloid leukaemia relapse Acute myeloid leukaemia (AML) has a high frequency of relapse and a high mortality rate associated with the persistence of leukaemia stem cells (LSCs). Natural killer (NK) cells are innate immune cells that detect surface ligands and trigger a cytotoxic response against tumour cells. NK cells are activated by inhibitory or activating ligands, including natural killer group 2D receptor ligands (NKG2DL), expressed on target cells after malignant transformation. However, LSCs evade detection by NK cells by repressing NKG2DL expression. Funded by the Marie Skłodowska-Curie Actions programme, the DIEAML project is searching for novel NKG2DL regulators in AML by combining single-cell transcriptomics and epigenomics of AML patient samples. The aim is to shed light on NKG2DL activation during malignant differentiation and to uncover potential links of this process to DNA hypermethylation. Show the project objective Hide the project objective Objective Acute Myeloid Leukemia (AML) is the most common adult leukemia, with a high frequency of relapse and mortality. After therapy, the persistence of rare leukemia stem cells (LSCs) with disease initiating and therefore stem cell-like properties is a likely cause for relapse. Therefore, novel therapeutic strategies to specifically eradicate LSCs are urgently needed. Natural Killer-cells (NK-cells) are innate immune cells capable of detecting cell surface ligands to trigger a cytotoxic response against diverse tumor cell types. NK-cells are activated either by missing inhibitory or activating ligands, such as known natural killer group 2D receptor ligands (NKG2DL), which become expressed on target cells upon cellular stress or malignant transformation. The groups of Drs. Trumpp, Lengerke and Salih recently described that LSCs evade the recognition from NK-Cells by repressing NKG2DL expression. Importantly, inhibition of Poly [ADP-ribose] polymerase 1 (PARP1) in a subclass of CD34+ AML patient samples reactivated NKG2DL expression and, when combined with allogeneic NK-Cell therapy, eradicated AML in xenotransplantation models. The goal of this proposal is to systematically discover novel NKG2DL regulators in AML to improve immunotherapeutic therapy options for a broad group of AML patients. I have identified monocytic differentiation and DNA hypermethylation as potentially opposing mechanisms of NKG2DL expression. I will combine single-cell transcriptomic and epigenomic interrogation of AML patient samples to discover how NKG2DL are activated during malignant differentiation and how these processes are impeded by DNA hypermethylation. These approaches, together with genome-wide CRISPR-dCas9 gain of function screens, will help identify master regulators of NKG2DL expression. Lastly, validation of these regulators in AML patient samples will expose vulnerabilities of AML for NK-cell based therapies and elaborate on the previously identified link with AML stemness. Fields of science social sciencessociologydemographymortalitynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesbasic medicineimmunologymedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologyleukemia Keywords Leukemia Stem Cells Acute Myeloid Leukemia NKG2DL regulation NK-Cell Therapy immune-evasion AML differentiation DNA hypermethylation AML single-cell transcriptomics methylomics CRISPR-dCAS9 Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2020 - Individual Fellowships Call for proposal H2020-MSCA-IF-2020 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG Net EU contribution € 162 806,40 Address Im neuenheimer feld 280 69120 Heidelberg Germany See on map Region Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
