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• W2745375235 abstract "Over the past years it has become clear that multiple genetically distinct subclones can co-exist in patients that suffer from acute myeloid leukemia (AML). These subclones often carry similar founder mutations, but upon leukemic evolution different secondary mutations arise in distinct subclones. Tools to prospectively isolate viable subclones to functionally study them are currently lacking. We performed transcriptome and quantitative proteome analysis on large cohorts of primary AML CD34+ samples and healthy CD34+ controls. Integration of these datasets resulted in a list of 60 plasma membrane (PM) proteins that were upregulated in specific subtypes of AML. Many of these were validated in independent cohorts of patients, and expression of specific markers was correlated to mutation status, disease progression and minimal residual disease. By using infinicyt, expression of multiple plasma membrane markers was linked to each other and this combinatorial approach was then used to perform principle component analyses in order to determine which (combination of) PM markers allows to identify distinct subpopulations based on PM expression profiles. While in 30-40% of investigated cases leukemias appear to be rather monoclonal, we have observed remarkable heterogeneity in clonal distributions in the remaining cases. Prospective sorting and subsequently targeted sequencing of these populations indeed confirmed the presence of different mutations in these subclones. Transcriptome studies revealed that gene expression profiles were also clearly distinct between subclones. We have begun to functionally analyse these subclones in vitro and in vivo. First, in order to further improve in vivo xenograft models we have implanted human Mesenchymal Stromal Cells (MSCs) with a mixture of matrigel and scaffolds in order to create a human bone marrow-like environment in the mouse. A large cohort of patient samples successfully engrafted in this model, covering all important genetic and risk subgroups. Furthermore, stem cell self-renewal properties were better maintained as determined by serial transplantation assays and genome-wide transcriptome studies, and less clonal drift was observed as determined by exome sequencing. The human leukemia xenograft mouse clinic that we have established will serve as an excellent resource for future studies aimed at exploring novel therapeutic approaches. For instance, we have recently utilized this model to investigate the role of polycomb group proteins in leukemia, and identified that the non-canonical PRC1.1 complex is critically important for leukemia development. Also, we have utilized these humanized niche mice to follow the kinetics of prospectively isolated (epi)genetically distinct subclones of individual patients." @default.
• W2745375235 created "2017-08-31" @default.
• W2745375235 creator A5011506752 @default.
• W2745375235 date "2017-09-01" @default.
• W2745375235 modified "2023-09-25" @default.
• W2745375235 title "Towards identification and targeting of leukemic stem cells and (EPI)genetically distinct subclones using humanized niche xenograft mouse models" @default.
• W2745375235 doi "https://doi.org/10.1016/j.exphem.2017.06.023" @default.
• W2745375235 hasPublicationYear "2017" @default.
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