An in vivo evaluation of aneuploid hematopoietic stem cell fitness

Abstract

Aneuploidy is an unbalanced cell state associated with developmental conditions such as Down syndrome (DS) as well as cancer, a disease of rapid proliferation. Studies of yeast, mouse and human cells harboring one extra chromosome have demonstrated that aneuploid cells show a number of common phenotypes in vitro, notably decreased proliferation. However, the precise role of aneuploidy in cancer has yet to be elucidated, in part due to lack of systematic in vivo model systems. Furthermore, evaluation of aneuploidy-associated phenotypes in vivo has been difficult because autosomal trisomy is generally embryonic lethal in mice. Here, I have evaluated hematopoietic stem cells (HSCs) derived from three aneuploid mouse models in vivo, two models of autosomal trisomy and one model of chromosome instability. By performing hematopoietic reconstitutions, I found that aneuploid HSCs have a range of fitness in vivo that correlates with the amount of extra DNA in each line. My results demonstrate that aneuploidy-associated cellular phenotypes are observed in vivo and in the context of a euploid organism. Additionally, I found that aneuploidy is well tolerated in the hematopoietic lineage under normal conditions in two of the three mouse models analyzed. However, even these relatively fit aneuploid cells begin to show more severe phenotypes upon repeated proliferative challenge. In humans, DS is associated with perturbations in the hematopoietic system, often resulting in childhood leukemia. Trisomy is also frequently observed in non-DS leukemias. Establishment of this model system enables future systematic dissection of the source of aneuploidy-associated fitness defects in vivo both in hematopoiesis and in the context of cancer.