Aneuploidy in Cancer: Lessons from Acute Lymphoblastic Leukemia
Authors: Oscar Molina, Maria Alba Abad, Francesc Solé, Pablo Menéndez
Journal: Trends in cancer (2020)

Although aneuploidy is a hallmark of cancer, our understanding of its contributions to cancer initiation and progression remains limited.Aneuploidy is physiologically associated with drastic cellular stress, but paradoxically favors tumor progression. Significant progress has been achieved over recent years in deciphering how aneuploid cancer cells self-adapt to promote tumorigenesis.Different forms of aneuploidy represent the initiating oncogenic lesion in ~35% of patients with B-cell acute lymphoblastic leukemia (B-ALL), especially in childhood B-ALL.Hyperdiploid B-ALL cells display a typical aneuploid-stress signature in which mitotic and chromosomal segregation defects are associated with impairments of the condensin complex and the aurora B kinase/chromosomal passenger complex (CPC), leading to cohesion defects and mitotic slippage. Aneuploidy, the gain or loss of chromosomes in a cell, is a hallmark of cancer. Although our understanding of the contribution of aneuploidy to cancer initiation and progression is incomplete, significant progress has been made in uncovering the cellular consequences of aneuploidy and how aneuploid cancer cells self-adapt to promote tumorigenesis. Aneuploidy is physiologically associated with significant cellular stress but, paradoxically, it favors tumor progression. Although more common in solid tumors, different forms of aneuploidy represent the initiating oncogenic lesion in patients with B cell acute lymphoblastic leukemia (B-ALL), making B-ALL an excellent model for studying the role of aneuploidy in tumorigenesis. We review the molecular mechanisms underlying aneuploidy and discuss its contributions to B-ALL initiation and progression. Aneuploidy, the gain or loss of chromosomes in a cell, is a hallmark of cancer. Although our understanding of the contribution of aneuploidy to cancer initiation and progression is incomplete, significant progress has been made in uncovering the cellular consequences of aneuploidy and how aneuploid cancer cells self-adapt to promote tumorigenesis. Aneuploidy is physiologically associated with significant cellular stress but, paradoxically, it favors tumor progression. Although more common in solid tumors, different forms of aneuploidy represent the initiating oncogenic lesion in patients with B cell acute lymphoblastic leukemia (B-ALL), making B-ALL an excellent model for studying the role of aneuploidy in tumorigenesis. We review the molecular mechanisms underlying aneuploidy and discuss its contributions to B-ALL initiation and progression. The gain or loss of whole chromosomes, termed aneuploidy (see Glossary), was identified as a distinct feature of cancer cells more than a century ago by the German zoologist Theodor Boveri [1.Boveri T. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris.J. Cell Sci. 2008; 121: 1-84Crossref PubMed Scopus (241) Google Scholar], and is now recognized as a major genomic insult in human cancers [2.Ben-David U. Amon A. Context is everything: aneuploidy in cancer.Nat. Rev. Genet. 2020; 21: 44-62Crossref PubMed Scopus (123) Google Scholar,3.Gordon D.J. et al.Causes and consequences of aneuploidy in cancer.Nat. Rev. Genet. 2012; 13: 189-203Crossref PubMed Scopus (537) Google Scholar]. Aneuploidy is observed more frequently than any other oncogenic or tumor-suppressor mutation, and is found in ~90% of solid tumors and ~60% of hematological malignancies [4.Duijf P.H. et al.Cancer cells preferentially lose small chromosomes.Int. J. Cancer. 2013; 132: 2316-2326Crossref PubMed Scopus (99) Google Scholar]. High-resolution, genome-wide analysis has revealed that ~25% of the genome in each cancer cell is affected by either chromosome-arm or whole-chromosome copy-number alterations [5.Beroukhim R. et al.The landscape of somatic copy-number alteration across human cancers.Nature. 2010; 463: 899-905Crossref PubMed Scopus (2504) Google Scholar]. Importantly, although recent studies have regarded both chromosome-arm gains and losses as aneuploidy, these are generated by different mechanisms. Thus, according to the classical definition of aneuploidy, we hereafter use the term 'aneuploidy' to refer to whole-chromosome gains and losses. Despite its high incidence, our understanding of the contribution of aneuploidy to cancer initiation and progression is limited for several reasons. First, large chromosomal changes lead to alterations in hundreds of genes and/or pathways, making it challenging to precisely identify those genes involved in tumorigenesis. Second, aneuploidy is often associated with chromosome instability (CIN) and/or microsatellite instability (MIN) [6.Bolhaqueiro A.C.F. et al.Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids.Nat. Genet. 2019; 51: 824-834Crossref PubMed Scopus (79) Google Scholar,7.Gryfe R. et al.Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.N. Engl. J. Med. 2000; 342: 69-77Crossref PubMed Scopus (1132) Google Scholar] that generate heterogeneous aneuploid karyotypes, making it difficult to distinguish the alterations that drive cancer growth from the numerous, apparently random, genetic alterations that occur during tumorigenesis. Third, aneuploidy is highly dependent on the cellular context and can both promote and inhibit tumor development in a tissue-specific manner [2.Ben-David U. Amon A. Context is everything: aneuploidy in cancer.Nat. Rev. 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Because cancer cells are often defective in pathways associated with cell-cycle control and genome stability, one possibility is that aneuploidy arises as a consequence of disruption of these pathways [13.Hernando E. et al.Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control.Nature. 2004; 430: 797-802Crossref PubMed Scopus (446) Google Scholar,14.Manning A.L. et al.Loss of pRB causes centromere dysfunction and chromosomal instability.Genes Dev. 2010; 24: 1364-1376Crossref PubMed Scopus (171) Google Scholar]. Another possibility is that aneuploidy per se acts as a tumor-initiating event. In this line, it was shown that introduction of specific chromosomes into cells induces replication stress and further genomic instability [15.Passerini V. et al.The presence of extra chromosomes leads to genomic instability.Nat. 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Of note, aneuploidy has been observed in some preneoplastic conditions such as Barrett's esophagus [19.Persons D.L. et al.Interphase cytogenetics of esophageal adenocarcinoma and precursor lesions.Cancer Genet. Cytogenet. 1998; 106: 11-17Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. In addition, Down syndrome (DS) individuals harboring constitutional trisomy of chromosome 21 have a 200-fold higher risk of developing hematological malignancies [20.Roy A. et al.Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 17579-17584Crossref PubMed Scopus (100) Google Scholar]. Aneuploidy may clearly exert a tumor-promoting role in some cancers. We review here the cellular and molecular mechanisms underlying aneuploidy, and discuss recent findings highlighting how aneuploidy contributes to the origin and progression of B-cell acute lymphoblastic leukemia (B-ALL). B-ALL represents an excellent model for studying the role of aneuploidy in tumor development because frequent chromosome gains and losses are observed as the sole genomic abnormalities in aneuploid B-ALL. The karyotype of most aneuploid tumors is within the range of diploid cells (46 chromosomes [4.Duijf P.H. et al.Cancer cells preferentially lose small chromosomes.Int. J. Cancer. 2013; 132: 2316-2326Crossref PubMed Scopus (99) Google Scholar]), suggesting that chromosome imbalances occur largely through sequential losses and gains of chromosomes through CIN from an initial diploid state or by chromosome losses after endoreduplication of genetic material. Mechanisms of CIN include those that reduce mitotic fidelity leading to chromosome segregation defects [21.Cimini D. et al.Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells.J. Cell Biol. 2001; 153: 517-527Crossref PubMed Scopus (384) Google Scholar]. During prometaphase, nuclear envelope breakdown allows chromosomes to attach to microtubule-based 'spindles' via kinetochores (Figure 1). During metaphase, chromosomes are concentrated in a region at the mid-plane of the bipolar mitotic spindle known as the metaphase plate. The back-to-back geometry of sister kinetochores on each chromosome favors the attachment of each chromatid to microtubules arising from opposite poles (amphitelic attachments), thus allowing proper chromosome bi-orientation and segregation [22.McIntosh J.R. Mitosis.Cold Spring Harb. Perspect. Biol. 2016; 8: a023218Crossref PubMed Scopus (46) Google Scholar]. However, the stochastic nature of kinetochore–microtubule attachments frequently leads to chromosome misattachments to the spindle [23.Thompson S.L. Compton D.A. Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors.Proc. Natl. Acad. Sci. U. S. 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Cell Biol. 2001; 153: 517-527Crossref PubMed Scopus (384) Google Scholar,25.Bakhoum S.F. et al.Deviant kinetochore microtubule dynamics underlie chromosomal instability.Curr. Biol. CB. 2009; 19: 1937-1942Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar]. The persistence of merotelic attachments in human cancer cells is mediated by two nonexclusive mechanisms – a decreased rate of error correction and an increased rate of merotely. Notably, some cancer cell lines display hyperstable merotelic kinetochore–microtubule attachments in early mitosis [25.Bakhoum S.F. et al.Deviant kinetochore microtubule dynamics underlie chromosomal instability.Curr. Biol. CB. 2009; 19: 1937-1942Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar], suggestive of inherent defects in correcting erroneous kinetochore–microtubule attachments. Accordingly, defects in several centromere/kinetochore proteins have been observed to reduce chromosome segregation efficiency by increasing the frequency of merotelic attachments and lagging chromosomes in anaphase [26.Abad M.A. et al.Structural basis for microtubule recognition by the human kinetochore Ska complex.Nat. Commun. 2014; 5: 2964Crossref PubMed Scopus (57) Google Scholar,27.Cimini D. et al.Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors.Curr. Biol. CB. 2006; 16: 1711-1718Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar]. However, mutations of kinetochore proteins in cancer are rare, presumably because these proteins are essential for life. However, imbalances in the levels of these proteins might act dominantly [23.Thompson S.L. Compton D.A. Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors.Proc. Natl. Acad. Sci. U. S. 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Residual cohesin is concentrated at centromeres where it is protected from removal by shugoshin-1 (from the Japanese 'guardian spirit'), resulting in the classical X-shaped mitotic chromosome [32.Morales C. Losada A. Establishing and dissolving cohesion during the vertebrate cell cycle.Curr. Opin. Cell Biol. 2018; 52: 51-57Crossref PubMed Scopus (47) Google Scholar] (Figure 1). Once all chromosomes have aligned at the metaphase plate, the protease separase removes centromeric cohesion and triggers anaphase onset, allowing separation of the sister chromatids to opposite spindle poles (Figure 1) [30.Uhlmann F. Nasmyth K. Cohesion between sister chromatids must be established during DNA replication.Curr. Biol. CB. 1998; 8: 1095-1101Abstract Full Text Full Text PDF PubMed Google Scholar,33.Uhlmann F. et al.Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast.Cell. 2000; 103: 375-386Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar]. 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The deleterious effects of aneuploidy in physiology are well established from yeast to mammalian cells [16.Williams B.R. et al.Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells.Science. 2008; 322: 703-709Crossref PubMed Scopus (413) Google Scholar,47.Torres E.M. et al.Effects of aneuploidy on cellular physiology and cell division in haploid yeast.Science. 2007; 317: 916-924Crossref PubMed Scopus (610) Google Scholar]. Aneuploidy is often lethal in multicellular organisms, and the few aneuploidies that do not cause lethality can reduce growth and trigger developmental abnormalities, leading to a substantial fitness cost under most circumstances [2.Ben-David U. Amon A. Context is everything: aneuploidy in cancer.Nat. Rev. Genet. 2020; 21: 44-62Crossref PubMed Scopus (123) Google Scholar]. 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Cell Biol. 2019; 21: 54-62Crossref PubMed Scopus (64) Google Scholar], which includes specific cellular responses such as lower proliferation rates, genetic and metabolic stress, and organismal effects including immune system activation (Box 1).Box 1Aneuploidy-Stress PhenotypeCellular Effects of AneuploidyThe most evident effect of aneuploidy is a reduction in cell proliferation and delayed cell-cycle progression at the G1–S transition [16.Williams B.R. et al.Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells.Science. 2008; 322: 703-709Crossref PubMed Scopus (413) Google Scholar,47.Torres E.M. et al.Effects of aneuploidy on cellular physiology and cell division in haploid yeast.Science. 2007; 317: 916-924Crossref PubMed Scopus (610) Google Scholar,71.Stingele S. et al.Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells.Mol. Syst. Biol. 2012; 8: 608Crossref PubMed Scopus (251) Google Scholar]. 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Lower proliferation rates are most likely a response to other cellular stresses associated with aneuploidy, such as gene expression and proteotoxic stresses. In addition, aneuploid cells have a characteristic gene expression signature in which gene expression networks are globally disturbed, similarly to the environmental stress response in yeast [47.Torres E.M. et al.Effects of aneuploidy on cellular physiology and cell division in haploid yeast.Science. 2007; 317: 916-924Crossref PubMed Scopus (610) Google Scholar]. In mammalian cells, the aneuploidy-stress response involves the conserved downregulation of pathways involved in nucleic acid metabolism, including replication, DNA repair, transcription, and RNA processing, as well as upregulation of pathways associated with autophagy, lysosomal pathways, and membrane metabolism, metabolic pathways such as glycolysis, and pathways associated with the inflammatory response [71.Stingele S. et al.Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells.Mol. Syst. Biol. 2012; 8: 608Crossref PubMed Scopus (251) Google Scholar]. The increased gene expression triggers proteotoxic stress as cells attempt to cope with the unbalanced excess of proteins generated by additional chromosome numbers. Proteotoxic stress is characterized by impaired protein folding, activation of degradation pathways, and accumulation of cytoplasmic protein aggregates with consequent accumulation of autophagosomes [74.Donnelly N. et al.HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells.EMBO J. 2014; 33: 2374-2387Crossref PubMed Scopus (71) Google Scholar,75.Santaguida S. et al.Aneuploidy-induced cellular stresses limit autophagic degradation.Genes Dev. 2015; 29: 2010-2021Crossref PubMed Scopus (85) Google Scholar]. These pathways allow aneuploid cells to maintain protein homeostasis against a background of elevated gene expression. In addition to metabolic stresses, aneuploidy generates further genomic instability, leading to cancer genome evolution and adaptation. Genomic instability in aneuploid cells is triggered by different mechanisms such as replication stress [15.Passerini V. et al.The presence of extra chromosomes leads to genomic instability.Nat. Commun. 2016; 710754Crossref PubMed Scopus (125) Google Scholar], chromosome bridge-fusion-breakage cycles [76.Tanaka H. Watanabe T. 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Indeed, the type I interferon pathway is consistently upregulated in aneuploid mammalian cells, and the expression levels of proinflammatory cytokines increase upon chromosome mis-segregation [79.Santaguida