Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

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.

Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia

“…8 Furthermore, TL was found to correlate with Ph-positivity of long-term culture initiating cells, LTC-IC measured by conventional cytogenetics (Tim H. Brümmendorf, T. L. Holyoake, P. M. Lansdorp, C. Eaves, unpublished results). Moreover, accelerated telomere shortening (typically observed in late CP CML) in myeloid neoplasia was found to be associated with genetic instability (reviewed in Ohyashiki et al 33 and Vajen et al 34 ) as well as with a characteristic inflammatory signature (termed telomereassociated secretory phenotype) potentially contributing to disease progression in a murine model of BCR-ABL 1 , telomerase knock-out cells. 35 Finally, effective execution of telomerase inhibition in a CML cell-line model was shown to be dependent of intact p53 signaling.…”

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

“…Telomeres, long tandem repeats of guanine-rich sequences, protect the ends of chromosomes and are progressively shortened after each cell division [53]. Once the telomere decreases beyond a critical length, the cell undergoes replicative senescence or apoptosis.…”

Increased likelihood of post-polycythemia vera myelofibrosis in Ph-negative MPN patients with chromosome 12 abnormalities

“…Interestingly, clonal and mutational complexity has been reported previously in a patient with LNK mutations at Chr12q24 [18]. Instability of chromosomal structure is a known factor in myeloid leukemogenesis [19]. Whether Chr12 patients in particular have a predilection for chromosomal instability cannot be determined by the current study.…”