The dicentric chromosome rob(15;21)c : mis-segregation and predisposition to cancer

Abstract

Robertsonian chromosomes are the most common constitutional translocation in humans, occurring in 1 in 800 of the general population. In 2014 it was discovered that carriers of the rare Robertsonian chromosome, rob(15;21)c, were strongly predisposed to developing a subtype of leukaemia, iAMP21-ALL (with ~2700-fold increased risk). In such cases, rob(15;21)c is dramatically rearranged to form a derivative chromosome that drives leukaemia. In silico modelling suggested that this derivative chromosome is produced by a catastrophic DNA damage event, chromothripsis, involving two copies of the rob(15;21)c chromosome. The reason for such a massive predisposition is not currently well understood. Here, I use cell biological techniques to explore the characteristics of the rob(15;21)c chromosome to better understand the mechanism causing iAMP21-ALL development. I show that rob(15;21)c is often actively dicentric, with the ability to assemble two kinetochores per sister chromatid. Despite the fact that rob(15;21)c is stably maintained in the cells of human carriers, I find that rob(15;21)c frequently mis-segregates during mitosis, at a much higher rate than chromosomes 15 and 21. I propose a mechanism in which the dicentricity of rob(15;21)c leads to an increased number of erroneous microtubule-kinetochore attachments which, if not resolved, often cause both rob(15;21)c chromatids to lag during anaphase. If this mis-segregation persists into telophase, then rob(15;21)c chromatids may enter a micronucleus, an environment previously shown to be a facilitator of chromothripsis. In summary, this work suggests that, due to the aberrant segregation tendencies of rob(15;21)c, carriers are predisposed to chromothripsis of rob(15;21)c and, in turn, the development of iAMP21-ALL.