MRDAML
Financiado
Deciphering the mechanistic basis of minimal residual disease and treatment resi...
Deciphering the mechanistic basis of minimal residual disease and treatment resistance in acute myeloid leukemia
Acute myeloid leukemia (AML) is one of the most aggressive and deadliest cancers with frequent relapse. Although initial therapies eliminate most AML blast cells, rare cells with leukemic stem cell (LSC) activity can persist and l...
Acute myeloid leukemia (AML) is one of the most aggressive and deadliest cancers with frequent relapse. Although initial therapies eliminate most AML blast cells, rare cells with leukemic stem cell (LSC) activity can persist and likely generate minimal residual disease (MRD) to re-initiate AML. Thus, targeting resistant LSCs during MRD might provide a unique opportunity to prolong remission and prevent relapse. However, because it is notoriously challenging to identify rare LSCs present within the vast number of normal blood cells during MRD, the phenotype, plasticity, function and mechanisms of LSCs in resistance and relapse remains poorly understood.Previous study from the Trumpp laboratory demonstrated a convergent pathway via hypermethylationn to drive initiation and progression of AML with IDH mutations or BCAT1 overexpression. However, the common and distinct mechanisms driving resistance in the two AML subtypes has not been explored, despite the observation that BCAT1 expression is upregulated in LSCs and upon relapse.Thus, in this proposal, I will first perform systematic phenotypic characterization of IDHmut/BCAT1hi AML cells to develop a high-quality LSC enrichment strategy. Subsequently, I will combine cutting edge single-cell multi-omics technologies to deeply characterize the mutational, transcriptomic and epigenetic dynamics of individual LSCs at diagnosis, MRD-positive remission and relapse. State of the art analytical methods will be used to integrate these data to dissect IDHmut/BCAT1hi AML with unprecedented resolution, examine the contribution of LSCs in MRD, and identify molecular regulators mediating LSC survival and resistance. Functional validation using pharmacological intervention, genomic editing in cell lines and patient-derived xenograft models will be performed to uncover causal relationships of the identified regulators. Overall, this work will lead to better mechanistic insight of MRD and therapy resistance in IDHmut/BCAT1hi AML.
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Duración del proyecto: 23 meses
Fecha Inicio: 2023-09-01
Fecha Fin: 2025-08-31
Fecha Fin: 2025-08-31
Línea de financiación: concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-09-01
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
HORIZON-MSCA-2021-PF-01-01:
MSCA Postdoctoral Fellowships 2021
Cerrada
hace 3 años
Líder del proyecto
DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5