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.

Expression and prognostic significance of chromatin modulators EHMT2/G9a and KDM2b in acute myeloid leukemia

“…Genomic instability is a hallmark of AML pathogenesis. Different chromosomal translocations were acquired during AML development and are considered an important tool in the anticipation of patients' treatment outcomes and prognosis 43 . One study showed that H3K9 methylation induced by EHMT2/G9a was enriched in genomic blocks that contain proto‐oncogenes and sites of chromosomal translocations in AML.…”

Case of Patient with AML with Complex Karyotype including Ultra-Rare t(4;8)(q32;q13), t(4;11)(q21;p15) and Familial Aggregation of Myeloid Malignancies

“…Chromosomal instability creates cytogenetic diversity and is a common feature in hematological malignancies, especially in all types of acute myeloid leukemia (de novo AML, secondary AML, and therapy-related AML), increasing the risk of the disease [15]. Considering the abnormal result of the examination of the patient's sister, we advised careful monitoring for hematological abnormalities and thorough examination if any alterations occur.…”

“…Metaphase cells from short-term 24 h unstimulated cultures were examined. Bone marrow cytogenetic testing exhibited complex karyotype described according to the International System of Human Cytogenomic Nomenclature (ISCN) 2020 as 46,XX,t(4;8)(q32;q13), t(4;11)(q23;p15),del(5)(q15q34) [15]/47,XX,sl,+der(4)t(4;8)(q?32;q?13). FISH test has confirmed interstitial deletion of the long arm of chromosome 5: nuc ish(D5S23,D5S721x2), (EGR1x1)[180/200], (D5S23,D5S721x2),(CSF1Rx1)[180/200] (Figure 1).…”

“…Metaphase cells from short-term 24 h unstimulated cultures were examined. Bone marrow cytogenetic testing exhibited complex karyotype described according to the International System of Human Cytogenomic Nomenclature (ISCN) 2020 as 46,XX,t(4;8)(q32;q13),t(4;11)(q23;p15),del(5)(q15q34) [15]/47,XX,sl,+der(4)t(4;8)(q?32;q?13). Translocation between the long arm of chromosome 4 in the q32 region and the long arm of chromosome 8 in the q13 region was observed in all analyzed metaphases.…”

In Silico Methods for the Identification of Diagnostic and Favorable Prognostic Markers in Acute Myeloid Leukemia

“…Polo-like kinase 4 (PLK4) plays a crucial role in controlling centriole duplication, and its deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability, and, consequently, tumorigenesis [56]. Genomic instability and cell cycle deregulation favor the rapid proliferation and clonal expansion of cells harboring oncogenic DNA alterations in AML [57][58][59]. The upregulation of hub genes controlling these processes reflects the tendency of hematopoietic precursor cells in bone marrow to accumulate DNA lesions and increase their proliferation rate at the expense of normal hemopoiesis, resulting in bone marrow failure.…”