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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.

Host institution

JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN
Net EU contribution
€ 605 645,00
Address
Theodor W Adorno Platz 1
60323 Frankfurt Am Main
Germany

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Region
Baden-Württemberg Stuttgart Stuttgart, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00

Beneficiaries (3)

JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN
Germany
Net EU contribution
€ 605 645,00
Address
Theodor W Adorno Platz 1
60323 Frankfurt Am Main

See on map

Region
Baden-Württemberg Stuttgart Stuttgart, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
MEDIZINISCHE HOCHSCHULE HANNOVER

Participation ended

Germany
Net EU contribution
€ 16 475,00
Address
Carl-neuberg-strasse 1
30625 Hannover

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Region
Niedersachsen Hannover Region Hannover
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00
MARTIN-LUTHER-UNIVERSITAT HALLE-WITTENBERG
Germany
Net EU contribution
€ 877 630,00
Address
Universitatsplatz 10
6108 Halle

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Region
Baden-Württemberg Stuttgart Stuttgart, Stadtkreis
Activity type
Higher or Secondary Education Establishments
Non-EU contribution
€ 0,00