Chromosomal instable T-ALLs induced by truncation of the SAC kinase Mps1 in combination with p53 loss display recurrent and clonal gains of specific chromosomes (chromosomes 4, 9, 14, and 15) detectable at the bulk level, indicating that ongoing chromosome instability is counteracted by selection that drives lymphoma cells toward favorable chromosome-specific copy number states. The majority of T-ALL cells within individual lymphomas carry these aneuploidies despite the continued CIN phenotype. [@bakker_single-cell_2016]
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Studies of Mps1 truncation-induced chromosomal instability have established that ongoing chromosome missegregation in unstable cells does not produce random karyotypic outcomes but instead generates convergent recurrent chromosome gains, suggesting that selective pressures act on highly aneuploid populations to favor specific chromosome copy number configurations. The mechanism underlying this convergence likely involves the same fitness constraints that drive aneuploid tumors to evolve specific adaptations such as Stat1 inactivation combined with Myc activation to suppress immune infiltration, indicating that certain chromosome gains confer proliferative advantages that allow aneuploid cells to overcome the general fitness costs associated with chromosomal imbalance. However, what remains contested is whether these recurrent gains emerge primarily through clonal selection of rare advantageous karyotypes or through deterministic biases in which chromosomes are gained during ongoing chromosomal instability, and single-cell sequencing studies revealing substantial karyotype heterogeneity within clonal populations suggest that chromosomal instability continues to generate diversity even after recurrent clonal patterns become detectable by bulk measurements.
Related
- Stat1 inactivation mechanism is conserved between mouse and human aneuploid cancers
- Multipolar divisions are rare and typically produce inviable progeny
- Different aneuploid cells share common fitness-related traits
- Aneuploidy impairs cell cycle progression in haploid yeast
- Extra chromosome genes drive aneuploid phenotypes through imbalanced protein composition
- Aneuploidy increases spontaneous tumor formation in aged animals
- Increased aneuploidy inhibits chemically and genetically induced tumorigenesis
- Aneuploid tumors inactivate Stat1 signaling with increased Myc activity
- Extra centrosomes correlate with chromosomal instability in tumors
- Stat1 loss combined with Myc activation alleviates CIN-induced immune infiltration
- CIN exists independently of classic mitotic defects in most cells
- Single-cell sequencing reveals karyotype heterogeneity in lymphomas
- Aneuploidy exhibits dual roles as oncogenic and tumor-suppressive
- CIN causality toward aneuploidy was previously unanswered
- CENP-E reduction generates aneuploidy and chromosomal instability
- Missegregation alone insufficient for aneuploid cell propagation