UBC Faculty Research and Publications

Centrosome Amplification Is a Potential Molecular Target in Paediatric Acute Lymphoblastic Leukemia Guo, Meiyun; Rever, Jenna; Nguyen, Phuong N. U.; Akella, Neha M.; Reid, Gregor S. D.; Maxwell, Chris

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer in children. Current treatments deliver a high survival rate, but often cause harmful and enduring side effects. New treatments are needed to address this clinical challenge and reduce relapse and long-term effects in children. This study investigates the centrosome clustering pathway as a target for cancer treatments in children with B-ALL. Cancer cells often have enlarged or extra centrosomes and require the centrosome clustering pathway to progress through cell division successfully. Our data reveals that when the centrosome clustering pathway is disrupted in B-ALL cells it causes cell death and produces a population of damaged refractory cells. The refractory cells have markers that make them more visible to the immune system and are therefore more easily targeted by immune-based therapies. Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children, with most cases arising from fetal B cell precursor, termed B-ALL. Here, we use immunofluorescence analysis of B-ALL cells to identify centrosome amplification events that require the centrosome clustering pathway to successfully complete mitosis. Our data reveals that primary human B-ALL cells and immortal B-ALL cell lines from both human and mouse sources show defective bipolar spindle formation, abnormal mitotic progression, and cell death following treatment with centrosome clustering inhibitors (CCI). We demonstrate that CCI-refractory B-ALL cells exhibit markers for increased genomic instability, including DNA damage and micronuclei, as well as activation of the cyclic GMP–AMP synthase (cGAS)-nuclear factor kappa B (NF-κB) signalling pathway. Our analysis of cGAS knock-down B-ALL clones implicates cGAS in the sensitivity of B-ALL cells to CCI treatment. Due to its integral function and specificity to cancer cells, the centrosome clustering pathway presents a powerful molecular target for cancer treatment while mitigating the risk to healthy cells.

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CC BY 4.0