Centrosome Amplification Is a Potential Molecular Target in Paediatric Acute Lymphoblastic Leukemia

Abstract

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.

Keywords

• paediatric acute lymphoblastic leukemia
• centrosome amplification
• multipolar division
• centrosome clustering
• genomic instability