Spårning av klonal evolution i leukemi- en cell i taget.
Tidsperiod: 2020-07-01 till 2023-06-30
Projektledare: Zahra Haider
Bidragstyp: Bidrag för anställning eller stipendier
Budget: 3 150 000 SEK
Acute lymphoblastic leukemia (ALL) accounts for the greatest number of deaths from childhood cancer overall. Hence there remains an urgent need to devise novel treatment strategies, particularly for the management of high-risk or relapsed refractory ALL. Treatment resistance in relapsed refractory leukemia is partly driven by intra-tumor heterogeneity shaped by clonal evolution. Therefore, it is imperative to study the dynamics of clonal evolution in leukemia and to characterize the cooperative mutational events that accompany leukemic transformation from early, pre-leukemic stem cell (pre-LSC) to a fully blown leukemia. This proposed study aims to track clonal evolution using a high risk, JAK3-driven T-cell ALL (T-ALL) model in vivo and to characterize the acquisition of oncogenic and non-oncogenic dependencies during malignant transformation. This 3-year postdoctoral project, undertaken at Children´s Cancer Institute, UNSW, Australia, will innovatively use a pre-clinical JAK3-mutant driven T-ALL mouse model in combination with state-of-the-art single-cell multi-omics (transcriptomics, genomics and cell surface phenotyping) and cellular lineage barcoding to longitudinally track the clonal evolution and development of leukemia. The successful completion of the project will simultaneously identify the cooperating genetic events and their order of acquisition during disease progression, which may then be exploited as potential targets for novel therapeutic strategies.