Abstract
Chromosomal instability (CIN), the increasing rate in which cells acquire new chromosomal alterations, is one of the hallmarks of cancer. Many studies highlighted CIN as an important mechanism in the origin, progression, and relapse of acute myeloid leukemia (AML). The ambivalent feature of CIN as a cancer-promoting or cancer-suppressing mechanism might explain the prognostic variability. The latter, however, is described in very few studies. This review highlights the important CIN mechanisms in AML, showing that CIN signatures can occur largely in all the three major AML types (de novo AML, secondary-AML, and therapy-related-AML). CIN features in AML could also be age-related and reflect the heterogeneity of the disease. Although most of these abnormalities show an adverse prognostic value, they also offer a strong new perspective on personalized therapy approaches, which goes beyond assessing CIN in vitro in patient tumor samples to predict prognosis. Current and emerging AML therapies are exploring CIN to improve AML treatment, which includes blocking CIN or increasing CIN beyond the limit threshold to induce cell death. We argue that the characterization of CIN features, not included yet in the routine diagnostic of AML patients, might provide a better stratification of patients and be extended to a more personalized therapeutic approach.
Highlights
Since Boveri’s theory that chromosome abnormalities promote cancer, studies have attempted to elucidate the mechanisms behind the origins of chromosomal aberrations [1]
Chromosomal instability (CIN) is defined as the increasing rate in which cells acquire new chromosomal alterations, aneuploidy is associated to the abnormal number of chromosomes in the karyotype at a specific point in time [29]
The protein mitotic arrest deficient 2 (Mad2) and cell division cycle protein 20 homologue (CDC20) overexpression and downregulation are frequently altered in many cancers and associated with CIN
Summary
Since Boveri’s theory that chromosome abnormalities promote cancer, studies have attempted to elucidate the mechanisms behind the origins of chromosomal aberrations [1]. CIN is defined as the increasing rate in which cells acquire new chromosomal alterations, aneuploidy is associated to the abnormal number of chromosomes in the karyotype at a specific point in time [29]. Jin and Burkard (2018) have associated CIN in AML patients with defects in the spindle assembly checkpoint (SAC). The inactivation of the entire mitotic checkpoint can generate chromosome mis-segregation leading to CIN or cell death [67,68] in various cancers [69,70,71]. Cells with NUP98 translocation contain aberrant securin (a regulatory protein of the metaphase-anaphase transition), leading to aneuploidy [80] Another APC/C protein with decreased expression in AML is Cdh, an antagonist regulator of SAC (which activates and mediates securin degradation). The high number of SAC alterations in AML cells can be associated with other dysfunctional chromosome segregation features
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