Chromosomal Instability in Acute Myeloid Leukemia

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.

Keywords: MYC; TP53; acute myeloid leukemia; aging; aneuploidy; centrosome dysfunction; chromosomal instability; complex karyotype; cytogenetic heterogeneity; synthetic lethality; telomere dysfunction; therapeutic targets.

Figure 1

CIN in AML can lead to many cytogenetic abnormalities, such as (A) trisomies, (B) telomere loss, (C) reciprocal translocations, (D) unbalanced translocations, (E) monosomies, (F) Dicentric chromosomes, (G) deletions, (H) ring chromosomes, (I) polyploidy.

Figure 2

AML patients can present various CIN features, such as Chromosome mis-segregation (1); Multipolar spindles (2); Dysfunctional cell cycle checkpoints (3); Telomere dysfunction (4); Defective DNA damage response (5); Chromosomal abnormalities associated with CIN (6). These unique CIN markers could be used in clinical practice (A) for better stratification of patients with complex karyotype (B) and combine new target therapies (C) for personalized treatments (D).