iAML-lncTARGET SIGNED
Targeting the transcriptional landscape in infant AML
Total Cost €
0EC-Contrib. €
0Partnership
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Project "iAML-lncTARGET" data sheet
The following table provides information about the project.
| Coordinator |
MARTIN-LUTHER-UNIVERSITAET HALLE-WITTENBERG
Organization address contact info |
| Coordinator Country | Germany [DE] |
| Total cost | 1˙499˙750 € |
| EC max contribution | 1˙499˙750 € (100%) |
| Programme |
1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC)) |
| Code Call | ERC-2016-STG |
| Funding Scheme | ERC-STG |
| Starting year | 2017 |
| Duration (year-month-day) | from 2017-06-01 to 2022-05-31 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | MARTIN-LUTHER-UNIVERSITAET HALLE-WITTENBERG | DE (HALLE (Saale)) | coordinator | 1˙483˙275.00 |
| 2 | MEDIZINISCHE HOCHSCHULE HANNOVER | DE (HANNOVER) | participant | 16˙475.00 |
Map
Project objective
Infant acute myeloid leukemia (AML) has a dismal prognosis, with a high prevalence of unfavorable features and increased susceptibility to therapy-related toxicities, highlighting the need for innovative treatment approaches. Despite the discovery of an enormous number and diversity of transcriptional products arising from the previously presumed wastelands of the non-protein-coding genome, our knowledge of non-coding RNAs is far from being incorporated into standards of AML diagnosis and treatment. I hypothesize that the highly developmental stage- and cell-specific expression of long non-coding RNAs shapes a chromatin and transcriptional landscape in fetal hematopoietic stem cells that renders them permissive towards transformation. I predict this landscape to synergize with particular oncogenes that are otherwise not oncogenic in adult cells, by providing a fertile transcriptional background for establishing and maintaining oncogenic programs. Therefore, the non-coding transcriptome, inherited from the fetal cell of origin, may reflect a previously unrecognized Achilles heel of infant AML, which I will identify with my expertise to understand and edit the AML genome and transcriptome. I will apply recent breakthroughs from various research areas to i) create a comprehensive transcriptomic atlas of infant AML and fetal stem cells, ii) define aberrant or fetal stage-specific non-coding RNAs that drive leukemia progression, and iii) resolve their features to probe the oncogenic interactome. After iv) establishing a biobank of patient-derived xenografts, I will v) evaluate preclinical RNA-centered therapeutic interventions to overcome current obstacles in the treatment of infant AML. Targeting the vulnerable fetal stage-specific background of infant AML inherited from the cell of origin may set a paradigm shift for cancer treatment, by focusing on the permissive basis required by the oncogene for inducing and sustaining cancer, rather than on the oncogene itself.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2019 |
Michelle Ng, Dirk Heckl, Jan-Henning Klusmann The Regulatory Roles of Long Noncoding RNAs in Acute Myeloid Leukemia published pages: , ISSN: 2234-943X, DOI: 10.3389/fonc.2019.00570 |
Frontiers in Oncology 9 | 2020-01-30 |
| 2019 |
Michaela Kuhlen, Jan-Henning Klusmann, Jessica I. Hoell Molecular Approaches to Treating Pediatric Leukemias published pages: , ISSN: 2296-2360, DOI: 10.3389/fped.2019.00368 |
Frontiers in Pediatrics 7 | 2020-01-30 |
| 2019 |
Sina Al-Kershi, Raj Bhayadia, Michelle Ng, Lonneke Verboon, Stephan Emmrich, Lucie Gack, Adrian Schwarzer, Till Strowig, Dirk Heckl, Jan-Henning Klusmann The stem cell–specific long noncoding RNA HOXA10-AS in the pathogenesis of KMT2A-rearranged leukemia published pages: 4252-4263, ISSN: 2473-9529, DOI: 10.1182/bloodadvances.2019032029 |
Blood Advances 3/24 | 2020-01-30 |
| 2020 |
Sarah Grasedieck, Christoph Ruess, Kathrin Krowiorz, Susanne Lux, Nicole Pochert, Adrian Schwarzer, Jan-Henning Klusmann, Mojca Jongen-Lavrencic, Tobias Herold, Lars Bullinger, Jonathan R. Pollack, Arefeh Rouhi, Florian Kuchenbauer The long non-coding RNA Cancer Susceptibility 15 is induced by Isocitrate Dehydrogenase mutations and maintains an immature phenotype in adult acute myeloid leukemia published pages: haematol.2019.23, ISSN: 0390-6078, DOI: 10.3324/haematol.2019.235291 |
Haematologica | 2020-01-30 |
| 2017 |
Maurice Labuhn, Felix F Adams, Michelle Ng, Sabine Knoess, Axel Schambach, Emmanuelle M Charpentier, Adrian Schwarzer, Juan L Mateo, Jan-Henning Klusmann, Dirk Heckl Refined sgRNA efficacy prediction improves large- and small-scale CRISPR–Cas9 applications published pages: 1375-1385, ISSN: 0305-1048, DOI: 10.1093/nar/gkx1268 |
Nucleic Acids Research 46/3 | 2019-09-02 |
| 2018 |
Marius Flasinski, Kira Scheibke, Martin Zimmermann, Ursula Creutzig, Katarina Reinhardt, Femke Verwer, Valerie de Haas, Vincent H. J. van der Velden, Christine von Neuhoff, C. Michel Zwaan, Dirk Reinhardt, Jan-Henning Klusmann Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study published pages: 1532-1540, ISSN: 2473-9529, DOI: 10.1182/bloodadvances.2018018945 |
Blood Advances 2/13 | 2019-09-02 |
| 2018 |
Mareike Rasche, Martin Zimmermann, Lisa Borschel, Jean-Pierre Bourquin, Michael Dworzak, Thomas Klingebiel, Thomas Lehrnbecher, Ursula Creutzig, Jan-Henning Klusmann, Dirk Reinhardt Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012 published pages: 2167-2177, ISSN: 0887-6924, DOI: 10.1038/s41375-018-0071-7 |
Leukemia 32/10 | 2019-09-02 |
| 2018 |
Raj Bhayadia, Kathrin Krowiorz, Nadine Haetscher, Razan Jammal, Stephan Emmrich, Askar Obulkasim, Jan Fiedler, Adrian Schwarzer, Arefeh Rouhi, Michael Heuser, Susanne Wingert, Sabrina Bothur, Konstanze Döhner, Tobias Mätzig, Michelle Ng, Dirk Reinhardt, Hartmut Döhner, C. Michel Zwaan, Marry van den Heuvel Eibrink, Dirk Heckl, Maarten Fornerod, Thomas Thum, R. Keith Humphries, Michael A. Rieger, Florian Kuchenbauer, Jan-Henning Klusmann Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia published pages: 1007-1016, ISSN: 0732-183X, DOI: 10.1200/JCO.2017.75.2204 |
Journal of Clinical Oncology 36/10 | 2019-06-13 |
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