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Targeting the transcriptional landscape in infant AML

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.

Call for proposal

ERC-2016-STG
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Host institution

JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN
Address
Theodor W Adorno Platz 1
60323 Frankfurt Am Main
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 605 645

Beneficiaries (3)

JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN
Germany
EU contribution
€ 605 645
Address
Theodor W Adorno Platz 1
60323 Frankfurt Am Main
Activity type
Higher or Secondary Education Establishments
MEDIZINISCHE HOCHSCHULE HANNOVER

Participation ended

Germany
EU contribution
€ 16 475
Address
Carl-neuberg-strasse 1
30625 Hannover
Activity type
Higher or Secondary Education Establishments
MARTIN-LUTHER-UNIVERSITAT HALLE-WITTENBERG
Germany
EU contribution
€ 877 630
Address
Universitatsplatz 10
6108 Halle
Activity type
Higher or Secondary Education Establishments