Chromosome structure and mitotic defects are major pathogenic mechanisms in hyperdiploid childhood B-ALL

High-hyperdiploid B-cell acute lymphoblastic leukemia (HHD-ALL) is defined by the presence of 51 – 67 chromosomes. HHD is thought to be the initiating oncogenic event in this subtype of B-ALL but the molecular mechanisms leading to HHD remain unknown. The aim of this work was to study the contribution of mitotic defects to the origin of HHD-ALL. We set out to study the contribution of mitotic defects in BCP-ALL primary samples. Results showed that HHD-ALL cells grow significantly slower than Non-HHD-ALL. Immunofluorescence analysis showed an accumulation of HHD-ALL cells in prometaphase coupled with defects on chromosome biorientation and increased chromosome missegregation rates. HHD-ALL cells showed high-order chromosome architecture defects with reduced SMC2 levels at chromosome scaffolds and Aurora B kinase misslocalization from the centromere. Aurora B defects were coupled with cohesion defects and an impaired spindle assembly checkpoint, leading to mitotic slippage and increased apoptotic rates. Results suggest that chromosome condensation defects associated with Aurora B misslocalization in prometaphase is a major pathogenic mechanism contributing to the origin of HHD-ALL.