Klonal mångfald i akut myeloid leukemi: Studier av dominanta och vilande leukemistamceller

Tidsperiod: 2014-07-01 till 2017-06-30

Projektledare: Karin Gustafsson

Finansiär: Vetenskapsrådet

Bidragstyp: Projektbidrag

Budget: 3 150 000 SEK

Recent evidence suggests that the leukemia stem cell (LSC) population in acute myeloid leukemia (AML) is diverse, consisting of both dominant and dormant clones. In many cases, dormant clones persist after treatment resulting in disease relapse. Successful treatment strategies are thus dependent on the elimination of both types of clones. The primary objective of this project is to characterize dominant and dormant AML LSC clones in the recently developed HUe reporter mouse. In his model, individual LSCs can be endogenously labeled with a distinct fluorescent color. This enables isolation of LSC clones for functional and molecular characterization. Earlier clonal tracing studies have been based on DNA sequencing, which have precluded analysis of gene expression and signaling. The HUe mouse therefore offers a unique opportunity to study the underlying mechanisms of AML clonal diversity. I will use this model determine the gene expression and signaling signatures of dominant and dormant AML LSC clones in order to identify regulatory networks present in both types of clones. Potential target pathways will be evaluated for their ability to affect LSC growth in a high-throughput screening assay. Finally, the most promising candidates will be knocked down in vivo to validate their effects on leukemia progression. This detailed understanding of the molecular basis for AML LSC clonal heterogeneity may aid in the development of new treatments that improve the survival of AML patients.