A somatic evolutionary model of the dynamics of aneuploid cells during hematopoietic reconstitution

Abstract

Aneuploidy is associated with many cancers. Recent studies demonstrate that in thehematopoietic stem and progenitor cell (HSPC) compartment aneuploid cells havereduced fitness and are efficiently purged from the bone marrow. However, early phasesof hematopoietic reconstitution following bone marrow transplantation provide awindow of opportunity whereby aneuploid cells rise in frequency, only to decline to basallevels thereafter. Here we demonstrate by Monte Carlo modeling that two mechanismscould underlie this aneuploidy peak: rapid expansion of the engrafted HSPC populationand bone marrow microenvironment degradation caused by pre-transplantationradiation treatment. Both mechanisms reduce the strength of purifying selection actingin early post-transplantation bone marrow. We explore the contribution of other factorssuch as alterations in cell division rates that affect the strength of purifying selection, thebalance of drift and selection imposed by the HSPC population size, and the mutationselectionbalance dependent on the rate of aneuploidy generation per cell division. Wepropose a somatic evolutionary model for the dynamics of cells with aneuploidy or otherfitness-reducing mutations during hematopoietic reconstitution following bone marrowtransplantation.\n\nSignificanceBone marrow transplantations (BMT) following ablative irradiation pose a great health risk. Its been shown that additionally the bone microenvironment is conducive to elevated frequencies of aneuploid cells in mice during bone marrow reconstitution post-BMT. As aneuploidy is linked with many cancers, we explore the reasons of such aberrant cell frequency peaks by Monte Carlo modeling. We demonstrate that elevated rates of aneuploidy early post-BMT are likely to be caused by reduced purifying somatic selection resulting from the expansion of the reconstituting population and the damage to stem cell niches caused by ablative radiation