Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

Abstract

Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.

Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System

“…Previous studies showed that aneuploidy is a rare occurrence in tissues even when chromosome segregation is compromised (Pfau et al, 2016) raising the possibility that mechanisms exist to eliminate cells with highly aberrant karyotypes in vivo . Our findings indicate that this is indeed the case.…”

“…Mice carrying a hypomorphic mutation in the spindle assembly checkpoint (SAC) component BUB1B ( BUB1b H/H allele), exhibit high levels of chromosome mis-segregation in all tissues where this has been analyzed (Baker et al, 2004). Yet, single cell sequencing revealed aneuploid cells to be exceedingly rare in regenerating tissues such as the intestine, skin and blood from these animals (Pfau et al, 2016). Whether aneuploid cells are outcompeted by euploid cells or whether mechanisms exist that eliminate aneuploid cells from tissues is not known.…”

Aneuploidy: Cancer strength or vulnerability?

“…In nonpathological conditions aneuploidy is well tolerated under “population flush” effects, when rapid cell expansion is needed (e.g., during embryogenesis) and in nonregenerating tissues, as brain and liver, in which the nonproliferative cellular status is protective against the potentially dangerous consequences of aneuploidy. On the contrary, aneuploidy is physiologically selected against in tissues that undergo self‐renewal, including the hematopoietic compartment, skin, and intestines . However, aneuploidy improves the survival rate under conditions of stress, including extreme temperature or pH, lack of nutrients, and incubation with chemotherapeutic or antifungal agents in budding yeasts .…”

Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis

“…Because aneuploidy is a rare occurrence in normal tissues (14) and even selected against in vivo (15), aneuploidy-associated stresses represent a unique opportunity to specifically eliminate cancer cells. A previously conducted, small scale, targeted proof-of-principle screen showed that compounds indeed exist that preferentially inhibit the growth of aneuploid cells (11) and spurred the larger scale effort to identify aneuploidy selective compounds described here.…”