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Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia
Institute of Cell and Molecular Pathology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 17 April 2013; in revised form: 17 June 2013 / Accepted: 25 June 2013 / Published: 4 July 2013
Abstract: Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions.
Keywords: chromosomal instability; myeloid leukemia; MDS; AML; telomeres; epigenetics; genetic instability
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Vajen, B.; Thomay, K.; Schlegelberger, B. Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia. Cancers 2013, 5, 857-874.
Vajen B, Thomay K, Schlegelberger B. Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia. Cancers. 2013; 5(3):857-874.
Vajen, Beate; Thomay, Kathrin; Schlegelberger, Brigitte. 2013. "Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia." Cancers 5, no. 3: 857-874.