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Targeting centrosome amplification in aneuploid B-cell precursor acute lymphoblastic leukemia

University of British Columbia

B-cell precursor acute lymphoblastic leukemia (B-ALL) remains the single largest contributor to relapse in the pediatric leukemia patient population and new treatments are sorely needed to address this clinical challenge. Centrosomes play an important role in cell division, and centrosome abnormalities are a common feature in cancer cells. Mitotic cells with centrosome amplification are likely to form multipolar spindles, which generally lead to cell death. Cancer cells, therefore, must cluster supernumerary centrosomes to form pseudo-bipolar mitotic spindles and maintain cancer cell viability. My study investigates the efficacy of emerging inhibitors of centrosome clustering as new therapies to target pediatric B-ALL cells. As normal cells do not need to use centrosome clustering pathways, these inhibitors have the potential for low toxicity to healthy and growing tissues. However, tumor cells often resist targeted therapies and it is prudent to expect tumor adaption. My study shows that centrosome clustering inhibitors induce genetic and genomic instability in refractory leukemia cells, including micronuclei, which localize the DNA sensor cGAS and increase production of pro-inflammatory signals. Thus, refractory tumor cells may be immunogenic and activate an innate immune response. Overall, these findings identify centrosome clustering inhibitors as potential therapies to kill tumor cells and condition an immunogenic population that may be targeted by immune-based therapies to achieve long-term immune protection.

Text

2020-05-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/74545

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/