Development of High Throughput Flowcytometric Assay for Immunophenotypical Quantification of Leukemic Stem Cells and Phenotype Based Drug Sensitivity Approach in Acute Myeloid Leukemia

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http://urn.fi/URN:NBN:fi:hulib-201908283358
Title: Development of High Throughput Flowcytometric Assay for Immunophenotypical Quantification of Leukemic Stem Cells and Phenotype Based Drug Sensitivity Approach in Acute Myeloid Leukemia
Author: Deb, Debashish
Contributor: University of Helsinki, Faculty of Biological and Environmental Sciences, Faculty of Biological and Environmental Sciences
Publisher: Helsingin yliopisto
Date: 2019
Language: eng
URI: http://urn.fi/URN:NBN:fi:hulib-201908283358
http://hdl.handle.net/10138/305029
Thesis level: master's thesis
Discipline: biotekniikka
Biotechnology
bioteknik
Abstract: There is significant reduction in number of approved drugs for acute myeloid leukemia in recent years. Partially it may be due to the failure of discovery and validation approach to new drugs as well as the complexity of the disease. Ex vivo functional drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia (AML). In ideal condition, an effective drug should eradicate the immature AML blasts, but spare non-malignant hematopoietic cells. However, current strategies like conventional cell viability assay fail to measure cell population-specific drug responses. Hence, development of more advanced approaches is needed. Using multiparameter, high-content flow cytometry (FC), we simultaneously evaluated the ex vivo sensitivity of different cell populations in multiple (10) primary AML samples to 7 FDA/EMA-approved drugs and 8 drug combinations. Amongst the 7 tested drugs, venetoclax, cytarabine and dasatinib were very cytotoxic with venetoclax had the highest blast-specific toxicity, and combining cytarabine with JAK inhibitor ruxolitinib effectively targeted all leukemic blasts but spared non-malignant hematopoietic cells. Taken together, we show that the ex vivo efficacy of targeted agents for specific AML cell population can be assessed with a cell phenotype, FC-based approach. Furthermore, we put an effort to analyze the potential of this assay and biomarkers to predict the clinical outcome of individual patients and future perspectives.
Subject: acute myeloid leukemia
High throughput flow cytometry


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