SUMMARY Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship between centrosome amplification, genomic instability and tumor development.

Haploinsufficiency of ribosomal proteins (RPs) has been proposed to be the common basis for the anemia observed in Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q [del(5q) MDS]. We have modeled DBA and del(5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14, respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. To address the hypothesis that RP loss results in impaired mRNA translation, we treated Rps19 and Rps14-deficient embryos with the amino acid L-leucine, a known activator of mRNA translation. This resulted in a striking improvement of the anemia associated with RP loss. We confirmed our findings in primary human CD34 ؉ cells, after shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that loss of Rps19 or Rps14 activates the mTOR pathway, and this is accentuated by L-leucine in both Rps19 and Rps14 morphants. This effect could be abrogated by rapamycin suggesting that mTOR signaling may be responsible for the improvement in anemia associated with L-leucine. Our studies support the rationale for ongoing clinical trials of L-leucine as a therapeutic agent for DBA, and potentially for patients with del(5q) MDS. (Blood. 2012; 120(11):2214-2224) IntroductionDiamond-Blackfan anemia (DBA; MIM# 105650) is a congenital bone marrow failure syndrome of childhood manifested as normochromic macrocytic anemia with absence or insufficient erythroid precursors in the bone marrow. 1,2 Twenty-five percent of DBA patients have mutations in the RPS19 gene, which encodes a component of the 40S ribosomal subunit. 3,4 A further 25% of DBA patients have been shown to have mutations in other ribosomal protein genes, 5 supporting the hypothesis that DBA is a disease of altered ribosome assembly or function. DBA shares a number of its clinical features with several other congenital syndromes that also carry heterozygous mutations affecting ribosome biogenesis, such as Shwachman-Diamond syndrome (SDS), cartilage-hair hypoplasia syndrome, and dyskeratosis congenita (DC) suggesting that all of these conditions share at least some common pathogenic mechanisms; they have thus been termed "ribosomopathies." 6 In addition, evidence suggests that the anemia associated with the 5q minus (5qϪ) syndrome (or myelodysplastic syndrome with loss of all or part of chromosome 5q [del(5q) MDS]), a distinct subtype of myelodysplastic syndrome results from somatic heterozygous loss of the ribosomal protein gene RPS14 in hematopoietic stem cells. 7,8 Efforts to understand why ribosomal protein haploinsufficiencies have such a specific and profound effect on erythroid development at the molecular level have focused on the activation and stabilization of p53 in response to ribosomal stress. 9 However, the precise mechanisms governing how p53 stabilization occurs in response to ribosomal protein haploinsufficiency have not been clearly defined. Furthermore, not all bone marrow samples from patients with del(5q) MDS or DBA sh...

Mitosis is a delicate event that must be executed with high fidelity to ensure genomic stability. Recent work has provided insight into how mitotic errors shape cancer genomes by driving both numerical and structural alterations in chromosomes that contribute to tumor initiation and progression. Here, we review the sources of mitotic errors in human tumors and their effect on cell fitness and transformation. We discuss new findings that suggest that chromosome missegregation can produce a proinflammatory environment and impact tumor responsiveness to immunotherapy. Finally, we survey the vulnerabilities exposed by cell division errors and how they can be exploited therapeutically.