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.

Fanconi Anemia (FA) is a disease characterized by genomic instability, increased sensitivity to DNA cross-linking agents, and the presence of clonal chromosomal abnormalities. This genomic instability can compromise the bone marrow (BM) and confer a high cancer risk to the patients, particularly in the development of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). The diagnosis of FA patients is complex and cannot be based only on clinical features at presentation. The gold standard diagnostic assay for these patients is cytogenetic analysis, revealing chromosomal breaks induced by DNA cross-linking agents. Clonal chromosome abnormalities, such as the ones involving chromosomes 1q, 3q, and 7, are also common features in FA patients and are associated with progressive BM failure and/or a pre-leukemia condition. In this review, we discuss the cytogenetic methods and their application in diagnosis, stratification of the patients into distinct prognostic groups, and the clinical follow-up of FA patients. These methods have been invaluable for the understanding of FA pathogenesis and identifying novel disease biomarkers. Additional evidence is required to determine the association of these biomarkers with prognosis and cancer risk, and their potential as druggable targets for FA therapy.

Chromosomes are organized in distinct nuclear areas designated as chromosome territories (CT). The structural formation of CT is a consequence of chromatin packaging and organization that ultimately affects cell function. Chromosome positioning can identify structural signatures of genomic organization, especially for diseases where changes in gene expression contribute to a given phenotype. The study of CT in hematological diseases revealed chromosome position as an important factor for specific chromosome translocations. In this review, we highlight the history of CT theory, current knowledge on possible clinical applications of CT analysis, and the impact of CT in the development of hematological neoplasia such as multiple myeloma, leukemia, and lymphomas. Accumulating data on nuclear architecture in cancer allow one to propose the three-dimensional nuclear genomic landscape as a novel cancer biomarker for the future.

Historically, hematological malignancies (HMs) and solid cancers were primarily attributed to cell-intrinsic mechanisms. However, overwhelming evidence highlights the crucial role of the tumor microenvironment in this process. Abnormalities in the bone marrow microenvironment (BMM) contribute to the development of HMs and affect patient outcomes. Bone Marrow Mesenchymal Stromal Cells (BM-MSCs) represent one of the key cell types within the BMM. Interestingly, a single specific gene mutation in BM-MSCs is sufficient to disrupt normal hematopoiesis and promote clonal malignant hematopoiesis in mice. Since a particular mutation may be sufficient, attention must also be given to chromosomal abnormalities (CAs), potentially affecting hundreds of genes. Notably, CAs have been identified in the majority of HMs BM-MSCs. CAs have been detected more frequently in BM-MSCs of HMs patients than in healthy donors. The primary explanation for CAs is chromosomal instability (CIN), a phenomenon characterized by increased rates of CAs. CIN can lead to abnormal gene expression, cellular senescence, and inflammation, altering MSCs. It may compromise their anti-tumorigenic functions and shift the BMM towards a supportive or protective state. Despite the importance of CAs and CIN, cytogenetic results in HM-MSCs appear controversial. This review discusses current studies, suggesting that some of the controversies may result from technical limitations. Furthermore, based on the high incidence of CAs and the lack of patterns (randomness), we suggest this is a case of CIN. Therefore, instead of looking for CAs patterns, we must focus on understanding the phenomenon of CIN in these cells. This includes verifying the frequencies of non-clonal CAs, looking for specific CIN mechanisms and distinguishing whether CIN is a driver or a consequence of HMs. To guide future research and address the existing knowledge gaps, we discuss potential approaches to the challenges in studying CAs in HM-MSCs.