cancers Review Chromosomal Instability in Acute Myeloid Leukemia Mateus de Oliveira Lisboa 1 , Paulo Roberto Slud Brofman 1, Ana Teresa Schmid-Braz 2, Aline Rangel-Pozzo 3,* and Sabine Mai 3,* 1 Core for Cell Technology, School of Medicine, Pontifícia Universidade Católica do Paraná—PUCPR, Curitiba 80215-901, Paraná, Brazil; [email protected] (M.d.O.L.); [email protected] (P.R.S.B.) 2 Hospital das Clínicas, Universidade Federal do Paraná, Curitiba 80060-240, Paraná, Brazil; [email protected] 3 Department of Physiology and Pathophysiology, University of Manitoba, Cell Biology, CancerCare Manitoba Research Institute, Winnipeg, MB R3C 2B7, Canada * Correspondence: [email protected] (A.R.-P.); [email protected] (S.M.); Tel.: +1-(204)787-4125 (S.M.) Simple Summary: Chromosome instability (CIN) is an increased rate where chromosome acquire alterations due to errors in cell division. CIN creates genetic and cytogenetic diversity and is a common feature in hematological malignancies such as acute myeloid leukemia (AML). Low to moderate levels of CIN seems to be well tolerated and can promote cancer proliferation, genetic diversity, and tumor evolution. However, high levels of CIN seems to be lethal, where enhancing CIN could improve AML treatment. However, little is known about CIN in AML. Our review focus on CIN studies in AML, their prognostic results, as well as the use of CIN as a therapeutic target in AML. Abstract: Chromosomal instability (CIN), the increasing rate in which cells acquire new chromoso- mal alterations, is one of the hallmarks of cancer. Many studies highlighted CIN as an important Citation: de Oliveira Lisboa, M.; mechanism in the origin, progression, and relapse of acute myeloid leukemia (AML). The ambivalent Brofman, P.R.S.; Schmid-Braz, A.T.; feature of CIN as a cancer-promoting or cancer-suppressing mechanism might explain the prognostic Rangel-Pozzo, A.; Mai, S. variability. The latter, however, is described in very few studies. This review highlights the important Chromosomal Instability in Acute CIN mechanisms in AML, showing that CIN signatures can occur largely in all the three major AML Myeloid Leukemia. Cancers 2021, 13, types (de novo AML, secondary-AML, and therapy-related-AML). CIN features in AML could also 2655. https://doi.org/10.3390/ be age-related and reflect the heterogeneity of the disease. Although most of these abnormalities cancers13112655 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. Academic Editor: Kirk J. McManus Current and emerging AML therapies are exploring CIN to improve AML treatment, which includes Received: 28 April 2021 blocking CIN or increasing CIN beyond the limit threshold to induce cell death. We argue that the Accepted: 26 May 2021 characterization of CIN features, not included yet in the routine diagnostic of AML patients, might Published: 28 May 2021 provide a better stratification of patients and be extended to a more personalized therapeutic approach. Publisher’s Note: MDPI stays neutral Keywords: chromosomal instability; acute myeloid leukemia; cytogenetic heterogeneity; aneuploidy; with regard to jurisdictional claims in complex karyotype; TP53; centrosome dysfunction; MYC; telomere dysfunction; therapeutic targets; published maps and institutional affil- aging; synthetic lethality iations. 1. Introduction Copyright: © 2021 by the authors. Since Boveri’s theory that chromosome abnormalities promote cancer, studies have Licensee MDPI, Basel, Switzerland. attempted to elucidate the mechanisms behind the origins of chromosomal aberrations [1]. This article is an open access article Chromosomal instability (CIN) is the increasing rate in which cells acquire new chromoso- distributed under the terms and mal alterations. Depending on the type of abnormalities, it can be classified into numerical conditions of the Creative Commons CIN (nCIN), characterized by chromosome gains and losses, and structural CIN (sCIN) Attribution (CC BY) license (https:// represented by chromosome translocations [2]. Importantly, CIN is one of the cancer hall- creativecommons.org/licenses/by/ marks [3]. CIN can promote selective advantage to cancer cells by increasing the probability 4.0/). Cancers 2021, 13, 2655. https://doi.org/10.3390/cancers13112655 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 2655 2 of 23 Cancers 2020, 12, x of novel chromosomal abnormalities, which can change the expression profile2 of 24 the genes regulating cell division and differentiation, resulting in high proliferation rates [3,4]. Recent studiesprobability have of shownnovel chromosomal a deep relationship abnormalities, of CIN which with can the change origin, the progression, expression profile and relapse in of the genes regulating cell division and differentiation, resulting in high proliferation many cancers [5–8]. rates [3,4]. Recent studies have shown a deep relationship of CIN with the origin, progres‐ sion, CINand relapse not only in occursmany cancers as a tumor-promotor [5–8]. mechanism but also as a tumor-suppressor mechanism.CIN not only This occurs observation as a tumor comes‐promotor from mechanism the evidence but also showing as a tumor that‐suppressor different levels of CINmechanism. lead to distinctThis observation outcomes. comes Moderate from the or lowevidence levels showing of CIN that are associateddifferent levels with of increased ratesCIN lead of genetic to distinct cancer-promoting outcomes. Moderate features. or low On thelevels other of CIN hand, are extreme associated levels with of in CIN‐ could leadcreased to decreasedrates of genetic cell fitnesscancer‐promoting or apoptosis features. [9]. The On the levels other of hand, CIN andextreme the siteslevels in of which it occursCIN could can lead also to indicate decreased different cell fitness outcomes or apoptosis [10 ].[9]. Therefore, The levels CINof CIN features and the notsites only in could refinewhich riskit occurs stratifications can also indicate but also different opens outcomes opportunities [10]. Therefore, for new CIN therapeutic features not approaches only in cancercould refine [9,11, 12risk]. stratifications but also opens opportunities for new therapeutic ap‐ proachesThe currentin cancer models [9,11,12]. for CIN involve telomere dysfunction, defective spindle assembly, sisterThe chromatid current models cohesion, for CIN DNA involve double-strand telomere dysfunction, breaks (DSB) defective repair, spindle genes involved assem‐ in the bly, sister chromatid cohesion, DNA double‐strand breaks (DSB) repair, genes involved cell cycle, and epigenetic regulators. These CIN mechanisms and their signatures can be in the cell cycle, and epigenetic regulators. These CIN mechanisms and their signatures largely found in acute myeloid leukemia (AML), a heterogeneous disease characterized can be largely found in acute myeloid leukemia (AML), a heterogeneous disease charac‐ byterized abnormal by abnormal proliferation proliferation and and accumulation accumulation of of myeloid myeloid precursor cells cells in in the the bone bone mar- rowmarrow [13]. [13]. AML AML can can be be classified classified as as de de novo novo AML, AML, secondary secondary AML (s (s-AML),‐AML), whose whose origin isorigin from is a from prior a hematologic prior hematologic disease, disease, and therapy-relatedand therapy‐related AML AML (t-AML), (t‐AML), which which arises as a resultarises as of a exposure result of exposure to alkalizing to alkalizing agents, agents, irradiation, irradiation, and and other other factors factors associated associated to prior therapyto prior therapy [14,15]. [14,15]. Regardless Regardless of the of classification, the classification, approximately approximately 55% 55% of AMLof AML patients pa‐ show chromosomaltients show chromosomal abnormalities abnormalities [16]. Cytogenetic [16]. Cytogenetic abnormalities abnormalities in AML in AML are are an an important prognosticimportant prognostic factor and factor are used and are for used risk-stratification for risk‐stratification and guide and guide treatment treatment definition defi‐ [17,18]. Fornition example, [17,18]. For a complex example, karyotype a complex karyotype (CK) is associated (CK) is associated with poor with prognosis poor prognosis [19]. In older patients[19]. In older (≥60 patients years), (≥60 only years), 10–44% only 10–44% of those of withthose ≥with3 cytogenetic ≥3 cytogenetic abnormalities abnormalities achieve achieve complete remission (CR) after therapy, and for those with ≥5 chromosome abnor‐ complete remission (CR) after therapy, and for those with ≥5 chromosome abnormalities, malities, the CR rates are significantly lower (7–26%) [20–25]. In this review, we will focus the CR rates are significantly lower (7–26%) [20–25]. In this review, we will focus on the on the mechanisms associated with CIN resulting in cytogenetic abnormalities (Summa‐ mechanismsrized in Figure associated 1), their prognostic with CIN impact, resulting and the in use cytogenetic of CIN as abnormalitiesa target among the (Summarized AML in Figuretypes. 1), their prognostic impact, and the use of CIN as a target among the AML types. 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,