Abstract
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.