Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo.
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.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Sarah J
SJ
Pfau
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Rebecca E
RE
Silberman
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kristin A
KA
Knouse
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Angelika
A
Amon
D000375:Aging / Q000235:genetics; D000782:Aneuploidy; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D007962:Leukocytes; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000235:genetics*; D016019:Survival Analysis
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases
aneuploidy; chromosomal instability; hematopoiesis; population flush hypothesis; single-cell sequencing