Chromosomal abnormalities of mesenchymal stromal cells in hematological malignancies

Genetic abnormalities in Hematological Malignancies (HMs) are key diagnostic markers in their respective Hematological Cells (HCs), serving as crucial indicators for identifying and classifying various HMs. Traditionally, the focus has been on these abnormalities within HCs due to their direct involvement in disease pathogenesis and prognosis [1]. However, a broader perspective has emerged over the last few years, highlighting overwhelming evidence for genetic abnormalities in HMs that are present in other bone marrow microenvironment (BMM) cell types [2].

The BMM is a complex network of cells that provides hematopoiesis and plays several roles in the body’s homeostasis [3]. The BMM is composed of several niches. The term niche, as proposed in 1978 by Schofield, refers to the specialized compartments in the BM that provide a place where Hematopoietic Stem Cells (HSCs) can survive, maintain quiescence, proliferate, and differentiate. The BMM comprises two primary niches: the endosteal and vascular niche [4]. The endosteal niche, crucial for hematopoiesis, contains osteoblastic cells that help maintain HSCs quiescence. The vascular niche, housing most HSCs, is essential for myelopoiesis and contains actively dividing HSCs [4]. Key cell types within these niches, including osteoblasts, endothelial cells, megakaryocytes, BM macrophages, adipocytes, and T lymphocytes, play diverse roles in regulating hematopoiesis and HSC maintenance. These cells, through their unique and overlapping functions, contribute directly or indirectly to the complex regulation of hematopoiesis and the dynamic nature of the BMM [5].

The genetic abnormalities found in these other cell types of the BMM in HMs were in some instances associated with a protective or a permissive BMM for the canonical HMs HCs [2]. Remarkably, genetic abnormalities in the BMM cells are shown to be associated with HMs development, progression, and relapse [6,7,8]. The ablation of only one factor in BMM is enough to cause HMs in mice. For example, mice with BMM lacking only retinoic acid receptor gamma (RARγ) or retinoblastoma protein (RB) develop myeloid HM [9, 10]. Additionally, transplanting normal BM cells into a Mind bomb-1 (Mib1)-null environment resulted in myeloid HM [11].

Another crucial line of evidence supporting the role of the BMM in HMs is provided by cases of donor-derived leukemia. Donor-derived leukemia arises when HSCs transplanted from a donor evolve into leukemia within the recipient. This phenomenon demonstrates that leukemia originates from the donor’s cells, not the recipient’s cells, suggesting abnormalities within the recipient’s BMM can induce leukemia in donor-derived HSCs [12, 13]. The crucial role of the BMM is also highlighted by the phenomenon of Clonal hematopoiesis of indeterminate potential (CHIP) during aging, in which there is clonal hematopoiesis of HSCs with HMs mutations. In CHIP does not necessarily leads to malignancy. The observation of CHIP indicates that BMM abnormalities might also be necessary for the transformation of clonally expanded HSCs into HMs [14].

An essential cell type in the BMM is the Mesenchymal Stromal Cells (MSCs), also known as Mesenchymal Stem Cells or Skeletal Stem Cells. The MSCs were initially isolated from the Bone Marrow (BM). Nowadays, MSCs have been isolated from various sources, such as adipose, dental, neonatal, and several other tissues. Most research has focused on using them as a source for cell therapy in regenerative medicine [15]. MSCs are multipotent cells capable of adipogenic, chondrogenic, and osteogenic differentiation and are involved in many different biological processes in their origin tissue [16].

The most extensively studied MSCs are those derived from bone marrow [15]. In the BMM, BM-MSCs play a pivotal role in supporting the hematopoietic niche within the bone marrow, primarily through the secretion of a diverse array of factors and the expression of specific surface molecules [5]. C-X-C motif chemokine 12 (CXCL12) and Stem Cell Factor (SCF) are among the secreted factors that are essential for HSC maintenance. CXCL12 ensures HSC homing and retention in the BM, while SCF promotes HSC survival and proliferation. Additionally, BM-MSCs express VCAM1 (Vascular cell adhesion protein 1), facilitating HSC retention, and produce angiopoietin-1, which maintains HSC quiescence through Tie2 receptor interaction. These contributions highlight the integral role of BM-MSCs in supporting HSCs by creating a conducive microenvironment within the BM [5].

BM-MSCs are key immunomodulators that regulate both innate and adaptive immune responses by inhibiting the activity of macrophages, neutrophils, natural killer cells, dendritic cells, and B and T lymphocytes [17]. In T cells they supress proliferation, block Th1/Th17 differentiation, and expand regulatory T cells (Tregs). MSCs also convert dendritic cells to a tolerogenic state that further amplifies Treg generation, shift macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) phenotypes, and attenuate IL-2/IL-15-driven NK-cell activation [17].

MSCs exert immunomodulatory effects that are amplified by pro-inflammatory signals. Interferon-γ (IFN-γ) together with TNF, IL-1α, or IL-1β triggers elevated expression levels of suppressive mediators, TGF-β, nitric oxide (NO), indoleamine-2,3-dioxygenase (IDO), TSG-6, prostaglandin E2, IL-1 receptor antagonist, IL-10, and an antagonistic CCL2 variant, and chemokines that recruit immune cells into a locally suppressive niche [17]. Moreover, microbial ligands recognized by toll-like receptors can also induce distinct MSC immune phenotypes [18]. Collectively, these observations position BM-MSCs as dynamic modulators that regulate innate and adaptive immunity in response to inflammatory cues.

The extensive research on the role of MSCs in the BMM has garnered significant interest within the cancer research field. Since then, differences in proteomic, transcriptomic, epigenetic, immunophenotypic, and metabolic profiles, as well as cytokine production, cellular senescence, and genetic alterations, have been identified in BM-MSCs from patients with HMs when compared to healthy donors (HD), as summarized in Fig. 1 [19]. Understanding the genetic aspects of HM-derived MSCs is fundamentally important because these cells are associated with many pathological aspects of the HMs [20]. Remarkably, a single specific gene mutation in MSCs (Sipa1 or Ptpn11) or mesenchymal osteoprogenitors (Dicer1) is sufficient to induce myeloid malignancy in mouse models [21, 22]. This underscores the relevance of CAs, which may impact the expression and function of hundreds of genes (Fig. 1).

While chromosomal abnormalities (CAs) can result from isolated events, they more commonly arise due to chromosomal instability (CIN). CIN refers to an elevated rate of CAs within a cell population. In most cases, CIN is caused by chromosome missegregation [23, 24]. CIN is often incorrectly equated with aneuploidy, defined as the gain or loss of whole chromosomes. However, aneuploidy does not necessarily indicate the presence of ongoing CIN, although it frequently arises as a consequence of CIN [24]. CIN represents a key prognostic marker associated with poor outcomes in multiple HMs. Patients with HCs presenting CIN are more likely to experience a relapse [25].

CIN is studied extensively due to its dual role: it can promote genetic diversity and dynamic adaptation, or alternatively, induce cellular stress responses such as senescence, apoptosis, and inflammation [26]. On one hand, CIN facilitates genetic diversity within cell populations by increasing the rate of genetic changes. This diversity can drive evolutionary dynamics, allowing the emergence of cell clones with unique genetic abnormalities and phenotypes. Such genetic variation may enhance the adaptability of clonal populations to microenviroment pressures [26]. On the other hand, CIN can lead to detrimental genetic changes that trigger immune responses, cell death pathways, including senescence, where cells stop dividing but remain alive, and apoptosis, programmed cell death [26].

CIN may contribute to explaining the observed phenotypic and functional abnormalities in BM-MSCs derived from HMs as summarized in Fig. 2. CIN has the potential to generate altered BM-MSCs capable of secreting factors that promote a microenvironment conducive to HM cell survival and expansion, which would not occur under homeostatic conditions. Specifically, in certain HMs subtypes, the detrimental effects of CIN may drive BM-MSCs into abnormal gene expression, senescence, and the release of pro-inflammatory signals, compromising their intrinsic cancer-suppressive functions or promoting pro-tumorigenic mediators. These alterations may establish a tumor-permissive and immunoprotective BMM [19]. As HMs progress, malignant cells often acquire resistance to regulatory constraints imposed by the BMM, including those mediated by BM-MSCs [27]. Moreover, CIN has been shown to elicit inflammatory responses, a well-established pathological hallmark of HMs (Fig. 2) [26, 28].

The most common byproduct and hallmark of CIN is the increased frequency of non-clonal CAs (NCCAs), which include both structural and numerical alterations occurring sporadically in individual cells. In the context of banding cytogenetics, NCCAs are defined as abnormalities observed in only a single metaphase, thus not meeting the criteria for clonality. To minimize artifacts introduced during metaphase preparation, whole chromosome gains or losses are typically excluded in this setting, and only structural changes are considered. Conversely, numerical NCCAs are reliably detected using interphase fluorescence in situ hybridization (FISH), where the intact nuclear membrane preserves native chromosomal content and reduces preparation-induced artifacts. These numerical changes reflect ongoing chromosomal missegregation and serve as sensitive indicators of dynamic genomic instability at the single-cell level [29]. In contrast, clonal CAs (CCAs) are defined as those present in ≥ 2 metaphases for structural abnormalities or ≥ 3 metaphases for numerical changes, based on the standard evaluation of 20 metaphases, as recommended by the International System for Human Cytogenomic Nomenclature (ISCN) [30].

Although a high NCCA burden is one of the most reliable cytogenetic hallmarks of CIN, these events are routinely dismissed as “background noise” in clinical practice, where the spotlight remains on recurrent, disease-defining CCAs, for example, the Philadelphia chromosome in chronic myeloid leukemia (CML) [31]. Omitting NCCAs from routine reports has fostered the misleading view that they are biologically irrelevant, when in fact their frequency provides a direct evidence of CIN, a key feature of many diseases, specially cancer [31]. This approach has led to their exclusion from most cytogenetic reports, thereby perpetuating the misleading notion that they are irrelevant to disease pathology. However, the presence of NCCAs is a key indication of CIN, one of the most important biological features in several diseases, especially in cancer [31].

Understanding CIN in HMs might help explain why the genetic expression profile and functional properties such as differentiation, immunomodulatory, tumor suppressor/promotion, and many others are different in HM MSCs. To date, cytogenetic findings related to MSCs from HMs have been considered controversial. This review examines these studies, emphasizing their limitations and exploring possible future directions. This analysis might help clarify existing knowledge gaps and illuminate the underlying controversies in this field. In certain HMs, the observed CAs may exemplify cases of CIN.

Multiple Myeloma (MM) is an HM characterized by the abnormal proliferation of plasma cells, secretion of an immunoglobulin known as M protein, and heterogeneous genetics [32]. MM remains one of the most clinically challenging HMs to treat. Increasing evidence implicates MM-derived MSCs (MM-MSCs) as key contributors to disease complexity and therapeutic resistance. MM-MSCs exhibit altered cytokine secretion profiles, reduced proliferative capacity, suppression of T-cell activity, and impaired osteogenic differentiation [33].

Transcriptomic analyses have revealed aberrant gene expression patterns in MM-MSCs compared to healthy donor-derived MSCs (HD-MSCs), with many dysregulated genes involved in critical processes of the BMM, including angiogenesis and bone remodeling, pathways integral to MM pathophysiology [34]. These findings suggest that genetic alterations in MM-MSCs may play a causal role in their phenotypic and functional reprogramming. A compelling example of malignant cell–stroma interaction involves the downregulation of DICER1 in MM cells, which induces senescence in neighboring MSCs. Senescent MSCs exhibit impaired differentiation capacity and enhanced ability to support MM cell survival and proliferation [35]. This exemplifies how a single gene-level perturbation can reprogram MSCs toward a tumor-promoting phenotype.

In most HMs, early cytogenetic investigations of BM-MSCs primarily aimed focused to identify the same CAs found in malignant HCs cells (Table 1). This strategy was employed to gain insights into the cell type and developmental stage at which such abnormalities originate. In MM, two studies used RT-qPCR and FISH in MM-MSCs to assess the presence of recurrent CAs, commonly found in plasma cells, in MM-MSCs. These studies did not detect the same abnormalities in MM-MSCs [36, 37]. However, the presence of altered gene expression in these cells raised the possibility that non-clonal or cryptic genetic abnormalities might underlie their altered phenotype.

In this context, Garayoa et al. (2009) demonstrated that MM-MSCs exhibit various non-recurrent genomic gains and losses. These were detected by array-based Comparative Genomic Hybridization (a-CGH), a genome-wide cytogenetic technique with a higher resolution than conventional cytogenetics, capable of identifying significantly smaller regions of genomic alteration. In this study, the resolution of a-CGH was ~1 Mb, and findings were further confirmed using FISH [37]. In addition, genes located in these regions presented abnormal expression. Moreover, the genomic abnormalities were primarily random. By contrast, HD-MSCs did not exhibit genomic abnormalities at this resolution [37].

While MM-MSCs are crucial to understanding the pathophysiology MM [38, 39], cytogenetic analysis of these cells is a relatively new field of investigation. CIN features, commonly observed in MM primary cells, have significant implications for patient prognosis. The changes in the microenvironment surrounding these cells are proposed as a critical factor contributing to the observed CIN signatures [32]. The randomness of CAs is the hallmark of CIN, and its presence in MM-MSCs may indicate the occurrence of this mechanism.

Investigating CIN in MM-MSCs is particularly significant in studying MSCs in HMs-MSCs because of the direct association observed between CAs and gene expression changes in MM-MSCs [37]. These findings underscore the role of MM-MSCs in shaping the tumor microenvironment and influencing disease progression and therapeutic response.

Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL) are HMs characterized by the clonal expansion and stepwise evolution of lymphoid cells. ALL predominates in the pediatric setting whereas CLL is mainly diagnosed in older adults. MSCs derived from the bone marrow (BM) of these patients (ALL-MSCs and CLL-MSCs, respectively) are increasingly recognized as active contributors to disease initiation, progression and chemoresistance [40,41,42,43,44].

In pediatric ALL, BM-MSCs retain a normal surface phenotype but exhibit increased adipogenic potential, reduced viability of healthy CD34⁺ hematopoietic progenitors, and a therapy-responsive proliferative arrest. Notably, this arrest inversely correlates with elevated secretion of bone morphogenetic protein-4 (BMP4), which is markedly upregulated in the presence of leukemic cells. These findings implicate BMP4-mediated MSC–leukemia crosstalk in the establishment of a protective leukemic niche within the BM microenvironment [40].

In B-cell CLL (B-CLL), BM-MSCs retain a normal phenotype, multilineage differentiation, T-cell immunosuppression, cytogenetics, and anti-apoptotic support for leukemic and normal B cells, yet display diminished reserves, apoptosis-related proliferative defects, aberrant secretion of SDF-1, BAFF, APRIL, and TGF-β1, and uniquely stimulate normal B-cell proliferation and IgG production, pointing to intrinsic MSC abnormalities that may fuel B-CLL pathogenesis [41].

BM-MSCs suppress the proliferation of normal hematopoietic progenitors but not of ALL pre-leukemic cells, thereby conferring a selective advantage that can promote leukemogenesis [42]. Moreover, by the attachment or detachment from MSCs, ALL cells can change their maturing states, which may increase their chemoresistance [43], and BM-MSCs further enhance ALL drug resistance via Wnt signaling [45]. ALL blasts also reprogram the MSC secretome to release higher levels of several cytokines [44]. In CLL, patient-derived MSCs display abnormal homing, adhesion molecule expression, and production of soluble factors; CLL cells, in turn, remodel the MSC compartment to generate a leukemia-supportive BM microenvironment [46].

The first cytogenetics studies in ALL-MSCs and CLL-MSCs focused on whether leukemia-defining CAs detected in HCs were also present in their MSCs counterparts (Table 1). Menendez et al. (2009) showed that among six hallmark CAs analyzed, only the MLL-AF4 translocation overlapped between ALL blasts and paired ALL-MSCs, and this overlap was observed exclusively in the youngest patients [47]. However, based on the flow cytometry data presented on their representative figure, the immunophenotypic profile of the purported MSCs did not fulfill the minimal criteria defined by the International Society for Cell & Gene Therapy (ISCT), suggesting potential contamination with non-MSC populations [48]. ISCT guidelines stipulate that ≥ 95% of cells should co-express CD105, CD73, and CD90, while ≤ 2% may express CD45, CD34, CD14/CD11b, CD79α/CD19, or HLA-DR [48]. To ensure rigor and reproducibility, it is recommended that authors report the exact percentages of positive and negative cells for each ISCT marker, ideally on a per batch or per sample basis, since averaging across samples can mask batch-specific immunophenotypic deviations that may impact interpretation. Moreover, providing only a single representative immunophenotype, as is often done, limits the ability to assess the consistency and purity of MSC populations across all samples in a given study [49].

Shalapour et al. (2010) analyzed MSCs isolated from pediatric B-ALL BM samples harboring TEL-AML1, E2A-PBX1 or MLL rearrangements in HCs. Using a multimodal cytogenetic platform combining interphase and metaphase FISH, whole-chromosome painting and patient-specific breakpoint sequencing, the authors demonstrated that the leukemia-defining fusion present in blasts was also detectable in 10–54% of paired MSCs. Remarkably, fusion-positive MSCs persisted during remission and even after myeloablative allogeneic stem-cell transplantation, and frequently exhibited additional numerical and structural CAs indicative of CIN [50]. However, immunophenotypic data were reported for only a single representative sample, limiting the ability to assess MSC purity, consistency, and reproducibility across the entire cohort. This limitation is particularly critical in studies reporting overlapping CAs between leukemic cells and MSCs, where rigorous validation is essential to rule out contamination.

The exclusive occurrence of such overlapping lesions in children, but not in adults, suggests a prenatal origin for ALL [51]. This finding could help explain the high incidence of secondary bone tumors, such as Ewing sarcoma, in survivors of pediatric ALL, which have been proposed to originate from MSCs [52]. Experimental expression of the EWSR1–FLI1 fusion in human or murine MSCs induces Ewing-like sarcomas, supporting MSCs as a potential cell of origin for this malignancy. If infant ALL-derived MSCs exhibit CIN, it may increase the likelihood of generating the EWSR1–FLI1 fusion along with cooperating abnormalities. However, Torres-Ruiz et al. (2017) showed that while CRISPR/Cas9 can induce this fusion in MSCs, the cells do not survive, unlike pluripotent stem cell derivatives. This suggests a developmental stage preceding MSCs as the more likely origin or that additional abnormalities are necessary, which could be provided in a CIN context [53]. Given the limited data on MSC purity in studies reporting overlapping CAs, these findings should be interpreted with caution and warrant further investigation.

As observed in MSCs derived from other HMs, random CAs have also been reported in ALL-MSCs at both diagnosis and relapse [50]. Although Campioni et al. (2012) did not detect CAs using G-banding, interphase FISH revealed aneuploidy in approximately 37% of ALL-MSCs and 53% of CLL-MSCs [54].

This discrepancy may reflect the greater sensitivity of FISH in detecting chromosomal abnormalities in senescent MSCs, which often fail to enter metaphase and are thus undetectable by G-banding. In addition, technical limitations may have contributed: the published metaphase spreads show incomplete membrane lysis and poor chromosomal dispersion, potentially reducing the quality and interpretability of the G-banding analysis [54]. Furthermore, the number of metaphases analyzed per sample was not reported in accordance with ISCN guidelines, preventing verification of whether an adequate number of cells was evaluated. The ISCN emphasizes reporting the number of analyzable metaphases as a key indicator of the success rate of genome-wide cytogenetic assays. Inadequate metaphase yields may compromise the sensitivity of G-banding and confound interpretations of chromosomal stability [30].

Conforti et al. (2013) reported contrasting findings in pediatric ALL, conducting an extensive cytogenetic analysis using G-banding, array-CGH, and FISH. They observed no CCAs in MSCs derived from ALL patients, either at diagnosis or during follow-up [40]. However, the karyotypes were not reported in accordance with ISCN guidelines, making it difficult to determine whether the absence of detectable abnormalities reflects true genomic stability or limitations in detection sensitivity.

Moreover, array-CGH may have overlooked hallmarks of CIN, as this technique lacks the single-cell resolution necessary to capture the cell-to-cell heterogeneity characteristic of CIN [29]. Pontikoglou et al. (2013) reported similar results in CLL, detecting no leukemia-specific or novel CCAs in CLL-MSCs [41]. The discrepancies between these studies and the findings of Campioni et al. [54] may be attributed to methodological differences. While Campioni et al. accounted for signal heterogeneity in their FISH analysis, directly reflecting the CIN phenotype, the later studies focused primarily on CCAs, potentially overlooking subtler forms of CAs heterogeneity.

Although ALL-MSCs and CLL-MSCs appear to play critical roles in the pathophysiology of these lymphoid HMs, their cytogenetic characterization remains significantly less developed than that of MSCs in HMs (Table 1). The detection of random aneuploidy suggests that the CIN phenotype may be more pronounced in CLL-MSCs than in ALL-MSCs, as indicated by the higher incidence of aneuploidy reported in the former. However, these observations are based on limited data and require further validation in larger, well-controlled cohorts. Nonetheless, research in this area is advancing, with multiple lines of evidence supporting a central role for MSCs in both ALL and CLL biology, particularly in modulating the bone marrow microenvironment, influencing leukemic cell survival, and contributing to chemoresistance [40, 41].

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm characterized by the Philadelphia chromosome, t(9;22)(q34;q11), which encodes the constitutively active BCR-ABL1 tyrosine kinase [55]. Although tyrosine-kinase inhibitors (TKIs) have markedly improved clinical outcomes during the past two decades, therapeutic challenges, particularly leukemic-stem-cell persistence and acquired resistance, remain. Growing evidence indicates that the BMM critically modulates CML pathogenesis, treatment response, and even early disease detection [46]. Within this niche, CML-derived MSCs (CML-MSCs) have emerged as key mediators of chemoresistance (reviewed in Dubois et al., 2020) [46].

Imatinib, the first-generation BCR-ABL1 TKI, up-regulates CXCR4 on CML cells, promoting their homing to CML-MSCs, where close cell-to-cell contact enhances leukemic surviva [56, 57]. CML-MSCs also display altered secretion of immunomodulatory factors [58]; for example, co-culture with CML mononuclear cells suppresses leukemic proliferation through interferon-α (IFN-α) release [59]. whereas IL-7–driven activation of the JAK1/STAT5 pathway confers additional drug resistance [60]. Despite these functional insights, the cytogenetic landscape of CML-MSCs has been far less explored than that of MSCs in other myeloid malignancies.

Reports of Philadelphia-positive hemangioblast-like and more primitive hematopoietic cells raised the possibility that MSCs might also harbor t(9;22) [61, 62]. Multiple groups therefore applied fluorescence in situ hybridization (FISH) and reverse-transcription PCR to cultured CML-MSCs, but BCR-ABL1 was not detected [63,64,65,66,67]. Two studies did report Philadelphia-positive cells; however, immunophenotyping pointed to macrophage contamination, and false-positive FISH signals could not be excluded [66, 68]. Although two investigations performed banding cytogenetics, they merely stated that t(9;22) was absent and did not provide complete karyotypes, precluding assessment of additional abnormalities [64, 67].

To date, cytogenetic studies in CML-MSCs have been largely restricted to searching for the canonical leukemic aberration present in hematopoietic cells. The paucity of genome-wide data limits evaluation of CIN or non-canonical changes that might influence the supportive role of MSCs in CML. Given the prognostic significance of CIN and CAs in CML hematopoietic compartments, systematic genomic profiling of CML-MSCs is warranted and may uncover new therapeutic targets.

Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem-cell disorders marked by ineffective hematopoiesis, one or more peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemia (AML). Increasing evidence implicates BM-MSCs of MDS patients as active contributors to disease initiation and progression (reviewed in Pontikoglou et al., 2023) [69]. Primary MDS blasts can reprogram healthy BM-MSCs in vitro into a pro-malignant BMM niche-like phenotype that favors clonal expansion [70]. In murine models, conditional deletion of Dicer1 in mesenchymal osteoprogenitors impairs differentiation and recapitulates key features of human MDS and AML while concomitantly down-regulating the Shwachman-Diamond–Bodian syndrome gene (SBDS) [21]. Consistent with these findings, patient-derived MDS-MSCs exhibit reduced expression of both DICER1 and SBDS [71].

Loss of SBDS in MSCs induces genotoxic stress in hematopoietic stem cells (HSCs) and heightens leukemic potential, paralleling Shwachman–Diamond syndrome (SDS), a congenital disorder characterized by high rates of bone-marrow failure and AML [21, 72]. In SDS, SBDS mutations engender a distinctive pattern of CIN that frequently involves chromosomes recurrently altered in MDS and AML [73]. Collectively, these observations show that a single gene perturbation in BM-MSCs can suffice to initiate MDS-like disease [22]. Because CAs can simultaneously dysregulate hundreds of genes, comprehensive cytogenetic profiling of MDS-MSCs is essential. For example, MDS-MSCs harboring trisomy 8 secrete aberrant levels of pro-inflammatory cytokines, underscoring the functional significance of MSC cytogenetics in MDS pathophysiology [74].

In the initial studies conducted on MDS-MSCs, the researchers questioned whether the same abnormalities present in the HCs could also be found in the MSCs of the same patients. Soenen-Cornu et al. (2005) applied FISH for the same genomic regions on both HCs and MSCs but did not find the same abnormalities involved in MDS [75]. However, abnormalities not involving these regions might have gone unnoticed.

Flores-Figueroa et al. (2005) were the first to examine MSCs from MDS patients by G-banding, identifying abnormal karyotypes in 55% of MSC cultures from individuals with refractory anemia, predominantly manifested as whole-chromosome losses. DNA analysis confirmed hypodiploidy. Notably, only patients whose HCs carried AKs exhibited CAs in their MSCs [76]. The same group later extended these findings, observing CAs in 67% of RA-derived MSCs, although individual karyotypes were not disclosed [77]. Consistent with this relationship, Han et al. (2007) detected no cytogenetic abnormalities in MSCs derived from RA patients whose hematopoietic cells displayed normal karyotypes [78]. Blau et al. (2007) found CAs in 44% of MDS-MSCs; 70% of these cases also showed abnormalities in HCs, supporting earlier observations [76, 78, 79]. They also identified structural CAs and extensive non-clonal translocations verified by multicolor FISH [79]. In contrast with the studies in which MSCs harboring AK were more frequent in MDS patients with HCs AK, Rathnayake et al. (2016) have shown that patients with HCs harboring CAs did not present CAs in the MSCs. The reason for that is not clear [80].

López-Villar et al. (2009) made important observations in MDS-MSCs. By employing a-CGH on MDS-MSCs (n = 33), they identified two distinct clusters of patients based on genomic abnormalities. One cluster consisted of all 5q- syndrome patients presenting only gains, while the other included the remaining MDS subtypes with both genomic gains and losses. Remarkably, abnormalities were found in all the cases in which array-CGH was applied, with gains being more recurrent than losses. FISH was used to confirm the results, and the genomic gains were validated. These abnormalities were not found in the HCs and T cells counterparts, providing evidence of non-constitutional abnormalities. Furthermore, to exclude the possibility of reporting abnormalities acquired during in vitro expansion, the same tests were applied to sorted MSCs. The uncultured MSCs also showed the same pattern of genomic abnormalities, confirming their findings. Suggesting that the CAs remain after cell culture [81]. By contrast, Kim et al. (2015) detected array-CGH abnormalities in only 1 of 17 MDS-MSC samples, attributing the low yield to the limited sensitivity of array-CGH for low-level mosaicism. Conventional G-banding, however, revealed clonal abnormalities in 30% of cases, although adequate metaphase numbers were obtained in only 65% of samples, suggesting that the true incidence may be underestimated [82].

Klaus et al. (2010) reported chromosomal gains in 4 of 13 MDS-MSC cultures, including trisomy 5 in three patients whose hematopoietic cells (HCs) carried 5q deletions, echoing earlier findings by López-Villar et al. (2009) [83]. Although trisomy 5 was visible by G-banding in only a single passage, FISH confirmed its persistence across passages, arguing against in-vitro artifact and supporting a clonal origin [81, 83]. Kouvidi et al. (2016) likewise observed that specific CAs appeared and disappeared between passages, evidence of ongoing CIN, and highlighted FISH as a sensitive method for detecting abnormalities missed by standard karyotyping. They further noted that MDS-MSCs bearing CAs tended to enter senescence, reinforcing the link between CIN and BMM dysfunction [84].

A persistent controversy in the cytogenetics of MDS-derived MSCs stems from reports that failed to identify CAs. Several early investigations employed only FISH and restricted their probe sets to regions already known to be altered in patients’ HCs. Because FISH interrogates only the targeted regions, lesions elsewhere in the MSC genome would remain undetected, so negative findings may simply reflect incomplete genomic coverage rather than true cytogenetic normality [75]. Zhao et al. (2012) likewise reported no CAs in cultured or sorted BM-MSCs from MDS patients, but their genome-wide G-banding analysis deviated from ISCN guidelines: instead of evaluating ≥ 20 metaphases per sample, they pooled 34 metaphases across 14 patients. Such aggregation complicates interpretation and limits reproducibility, casting doubt on the conclusion that MDS-MSCs are cytogenetically normal [85]. Corradi et al. (2018) also failed to detect CAs; however, their study examined only three MDS-MSC samples with a limited FISH probe panel, again raising the possibility of false-negative results driven by methodological constraints rather than genuine genomic stability [86]. Therefore, the absence of CAs may reflect technical limitations rather than true genomic stability.

The reported frequency of CAs in MDS-MSCs varied widely across studies. Using G-banding, Blau et al. (2011) identified CAs in only 12% of cases, the lowest prevalence reported to date, and confirmed these findings with FISH [87]. At the opposite extreme, Song et al. (2012) observed CAs in 64% of MDS-MSC cultures, a high rate attributed to their exceptional yield of analyzable metaphases [88]. Such variability often reflects the challenge of obtaining adequate metaphase spreads, as illustrated by Azuma et al. (2017), who detected CAs in just 2 of 5 samples because few metaphases were evaluable [89]. Complementary techniques can mitigate this limitation: Xiong et al. (2015) uncovered CAs in 30% of MDS-MSC samples exclusively by interphase FISH, lesions that conventional karyotyping had missed [90].

CAs in HD-MSCs are exceedingly rare, as demonstrated by numerous studies on BM-MSCs used in regenerative medicine. However, in one of the largest and earliest HD cohorts, Klaus et al. (2010) reported a single case of trisomy 5, an unusual but notable finding, potentially attributable to the advanced age of the donor [83]. Similarly, Kouvidi et al. (2016) identified trisomy 5 in two HDs aged 80 and 59, respectively [91]. While CAs in HD-MSCs are rare, the recurrence of trisomy 5 in independent studies suggests it may represent a low-frequency, age-associated aberration observed even in otherwise healthy individuals. These findings, however, do not diminish the significance of CAs in MSCs derived from patients with HMs, especially given the strong association between HMs and aging [92].

The stochastic appearance of both CCAs and NCCAs in MDS-MSCs is suggestive of underlying CIN. Supporting this, molecular signatures of CIN beyond random CAs have been detected in MDS-MSCs. One key mechanism driving CIN is centrosome dysfunction, often resulting from aberrations in Aurora kinases. Oliveira et al. (2013) reported differential expression of Aurora kinases in both HCs and MSCs from MDS patients, with aberrant expression significantly associated with samples exhibiting abnormal karyotypes in both compartments [93].

The cytogenetics of MDS-derived MSCs (MDS-MSCs) is more extensively characterized than that of MSCs from other hematologic malignancies (Table 1). Most studies report a relatively high incidence of CAs in MDS-MSCs. Although this remains a topic of debate, studies that identified overlapping CAs between HCs and MSCs often analyzed MSCs with immunophenotypes that did not conform to the minimal criteria established by the ISCT, raising concerns about cell purity.

Importantly, CAs have been identified in MDS-MSCs from patients regardless of whether their HCs exhibit normal or abnormal karyotypes. The body of literature on MDS-MSCs provides compelling evidence not only for the presence of CAs but also for features consistent with CIN. The abnormalities observed are predominantly non-clonal and random, although clonal abnormalities have also been reported, some persisting through multiple passages, while others emerge and disappear, consistent with dynamic CIN.

While numerical abnormalities are most commonly described, structural alterations such as translocations may be underreported due to the technical difficulty of acquiring sufficient high-quality metaphases. Additional hallmarks of CIN have also been detected in MDS-MSCs, including aberrant expression of genes involved in genome stability (e.g., DICER1, SBDS), centrosome dysfunction signatures, and CAs that correlate with functional outcomes such as cellular senescence. Notably, CIN features in MDS-HCs are associated with an increased risk of progression to AML, underscoring the clinical relevance of CIN in both stromal and hematopoietic compartments.

AML is an aggressive heterogeneous myeloid malignancy characterized by the rapid expansion of aberrant myeloid progenitor cells [25]. A major challenge in AML therapy is the development of resistance, in which the BMM plays a central role. Increasing evidence implicates MSCs derived from AML patients (AML-MSCs) as active participants throughout all disease stages [94].

Similar to MDS-MSCs, AML-MSCs exhibit a range of functional, differentiation, genetic, and epigenetic abnormalities. However, their precise role in leukemogenesis remains under active investigation and debate [94]. Interestingly, MSCs have demonstrated anti-tumorigenic effects in AML cell lines [95,96,97], while in primary AML cells, BM-MSCs have been shown to confer anti-apoptotic and growth-promoting effects [98]. Furthermore, MSCs can transfer mitochondria directly to AML cells, enhancing their metabolic capacity and contributing to chemotherapy resistance [99].

Notably, AML blasts can actively reprogram MSCs, altering their expression and secretion of factors that facilitate leukemic progression and relapse [100]. These observations underscore a bidirectional interaction between AML cells and MSCs: while MSCs contribute to the formation of a supportive or protective BMM, they are also susceptible to manipulation by leukemic cells [94]. As with other hematologic malignancies, AML-MSCs display genetic abnormalities, including CAs.

The two studies by Blau and colleagues on AML-derived MSCs illustrate how analytical conventions can either expose or obscure CIN [79, 87]. In their 2007 study, every structural abnormality. including those seen in a single metaphase, was recorded as a legitimate event. With that permissive definition, 6 of 11 AML-derived MSC cultures (55%) were judged abnormal, and more than 70% of the aberrations were NCCAs that appeared once in a panel of 20 mitoses. Only two cultures satisfied ISCN criteria for clonality ≥ 2 identical structural or ≥ 3 identical numerical events. Thus, the dominant cytogenetic signal was the raw NCCA burden, an evidence for ongoing CIN [79].

By 2011, the same group had adopted stricter ISCN criteria and required FISH confirmation for clonal aberrations [87]. Under this filter, the frequency of detectable abnormalities in AML-MSCs fell to 10 of 51 cases (20%), essentially the ~18% one would obtain by rescoring the 2007 dataset with identical criteria. Notably, half of the abnormal cases in the 2011 study involved therapy-related AML, suggesting a role for accumulated genotoxic stress. However, by focusing exclusively on CCAs, the study inherently excluded single-cell events, thereby underestimating early, low-fitness CIN clones [87].

Together, the two papers underscore a central message of this review: NCCAs are not “background noise” but the most sensitive cytogenetic read-out of active CIN. Ignoring them, still common practice in diagnostic laboratories, masks the true scale of genome instability in the leukemic BMM [101]. When NCCAs are included in the analysis, more than half of AML-MSC cultures exhibit evidence of CIN; when excluded, only one-fifth appear cytogenetically abnormal. This discrepancy is methodological, not biological.

Senescence is a frequent feature of HM-derived MSCs and can markedly reduce the yield of analyzable metaphases for conventional cytogenetics [19]. Kim et al. (2015) reported an insufficient metaphase harvest in several AML-MSC cultures because of accelerated senescence. Although clonal abnormalities detected by G-banding were validated by FISH, they were missed by array-CGH owing to low-level mosaicism, underscoring the advantage of interphase-based techniques for senescent samples. The overall CA frequency was slightly higher in AML-MSCs than in MDS-MSCs (6% vs. 5%) in that study [82], highlighting the need for complementary interphase approaches when metaphase quality is poor.

The purported “controversy” surrounding overlapping CAs in AML HCs and MSCs appears to stem from methodological shortcomings. In Huang et al. (2015), two AML-MSC cultures carried the same CAs as the corresponding HCs; however, these lesions were present in every analyzed cell and are therefore likely constitutional rather than somatic. In addition, the MSC immunophenotypes in these cases did not satisfy ISCT criteria, suggesting hematopoietic contamination [48, 102]. Thus, current evidence does not convincingly demonstrate true somatic overlap of CAs between AML-MSCs and leukemic blasts.

Negative cytogenetic findings in AML-MSCs are likewise attributable to technical limitations. Guardia et al. (2015) reported no CAs in a cohort of 46 patients, yet conventional karyotyping was attempted in only 63% of cultures and the number of metaphases scored per sample was not disclosed, both deviations from ISCN guidelines. Since banding cytogenetics was applied in a small number of cases, a low number of metaphases might also be expected per case [103]. Similarly, Azuma et al. (2017) detected CAs in 2 of 5 AML-MSC samples; two “normal” cases were based on only 1.5 and 6 metaphases, respectively, rendering false-negatives likely [89].

Further highlighting the challenges in assessing cytogenetic abnormalities in AML-MSCs, Zhang et al. (2021) conducted transcriptomic analyses revealing over 1800 upregulated and more than 1900 downregulated genes. Despite these profound expression differences compared to HD-MSCs, the authors did not provide full ISCN-compliant karyotypic data. They reported only “minimal differences” in karyotype, yet their single representative karyogram clearly shows structural and numerical abnormalities. This discrepancy underscores the importance of comprehensive cytogenetic characterization to accurately correlate CIN features with molecular and functional alterations in AML-MSCs [104].

Compared with MDS, the cytogenetic landscape of AML-MSCs remains poorly defined. Available studies, particularly those with adequate metaphase numbers or interphase FISH, suggest that AML-MSCs may harbor CAs at least as frequently as, and possibly more often than, MDS-MSCs. Because CIN in AML blasts carries significant prognostic weight, a systematic, genome-wide evaluation of AML-MSC cytogenetics is warranted. Apparent overlaps between MSC and HC karyotypes generally coincide with inadequate lineage purity, while reports of “normal” MSC karyotypes often reflect suboptimal metaphase yields or limited genomic coverage rather than true genomic stability.

Across HMs, cytogenetic profiling of patient-derived MSCs invariably reveals CIN manifested as both CCAs and a far larger burden of NCCAs (Table 1). Murine models underscore their pathogenic potential: a single engineered gain- or loss-of-function mutation in Ptpn11, Dicer1 or other stromal genes is sufficient to trigger myeloid disease, illustrating how genetic disruption can reprogramme the microenvironment. Randomly distributed abnormalities might provide a mechanistic basis for the broad transcriptomic, proteomic and functional perturbations documented in HM-derived MSCs.

Early reports of identical, recurrent CAs in paired HCs and MSCs suggested a common malignant progenitor; however, most subsequent work contradicts this. In rigorously purified cultures, matched CCAs are vanishingly rare. When overlap is claimed, the putative MSC fraction almost always violates ISCT purity criteria, pointing to adherent HC carryover. A representative example is Huang et al. (2015), in which “AML-MSCs” harboring a leukemic CCA contained ~15–20% CD45⁺ cells, ~40% CD34⁺ cells, and <80% CD105⁺, well outside the ISCT thresholds ( < 2% hematopoietic markers; ≥95% CD105⁺) [102].

CIN could, in principle, downregulate MSC surface antigens, but the weight of evidence indicates that apparent overlaps reflect residual HC contamination. Definitive resolution will require deliberately inducing CIN in highly purified donor MSCs, followed by longitudinal single-cell assays that co-profile surface markers and genomes. If CIN alone cannot reproduce the marker erosion seen in patient samples, the contamination hypothesis collapses.

A full ISCN compliant karyotype remains essential, but it is insufficient when CIN is the endpoint. Authors should also report the frequency and spectrum of NCCAs, quantitative indices of chromosomal heterogeneity, and the metaphase success rate, which calibrates false negative risk. These additions enable meta analysis and fair comparison between studies.

Whether MSC CIN is an initiating event, a by product of malignant evolution, or both remains unresolved. In therapy-related HMs, stromal CIN probably reflects diffuse DNA damage from cytotoxic therapy. In de novo disease the picture is complex: age related decline in genome maintenance explains part of the burden, yet extensively aberrant MSCs are documented in young, treatment naïve patients, implicating additional drivers.

Murine evidence for causation indicates that single MSC intrinsic lesions can precipitate myeloid malignancy. One mechanism is inflammation: under ribosomal stress, MSCs activate a p53-dependent inflammatory programme that raises mitochondrial ROS and DNA double strand breaks in haematopoietic stem/progenitor cells. Disabling this abrogates genotoxic stress, establishing its necessity for mutagenesis [72]. Clinically, elevated expression of these mediators identifies MDS patients who progress rapidly to AML, implicating pro-inflammatory MSCs in establishing a pre-leukemic niche. Another proposed hypothesis is that the pathways driving CIN in HCs may also disrupt MSCs, as both cell compartments exhibit dysregulated expression of genes involved in chromosome segregation [93].

Non–cell autonomous CIN transfer is exemplified by irradiated MSCs induce DNA damage and karyotypic change in co-cultured CD34⁺ cells, proving that stroma can propagate CIN [105]. Gain-of-function Ptpn11 mutations trigger abnormal mitosis and sensitize HCs to DNA damage [106]; whether mutant MSCs themselves develop CIN and export it to HCs remains unexplored. Genomically unstable MSCs may also remodel the niche through cGAS–STING activation, as reported for CIN positive solid tumor cells [107], but this pathways is unexplored in HMs.

The differentiation potential abnormalities become evident when genetic damage perturbs MSC fate [108]. For example, Dicer1 loss blocks osteogenesis and drives MDS/AML, while AML-MSCs often exhibit a bias toward adipogenesis, a state that favors leukemic proliferation [21, 35, 109]. Because CIN impairs lineage commitment in embryonic stem cells [110], CIN in MSCs is likely to exacerbate such defects, an idea that awaits direct testing.

Common downstream consequences of CIN, such as abnormal gene expression profiles, senescence, and inflammation, are all documented in HM-derived MSCs. We therefore propose a model (Fig. 2) in which CIN-positive MSCs lose tumor-suppressive functions and instead cultivate a HMs-permissive BMM trough the mentioned abnormalities.

Senescence can both arise from and complicate the detection of CIN. Low mitotic indices leave fewer than 20 analyzable metaphases, inflating false negatives and introducing survivor bias toward the least-damaged cells. Our laboratory mitigates this by cell cycle synchronization, coupled with CIN assays that bypass mitosis. Multiplex interphase FISH combined with high content imaging quantifies micronuclei, anaphase bridges and other CIN surrogates across tens of thousands of nuclei. Live cell micronucleus assays, scDNA seq and optical mapping extend resolution to senescent subsets.

To generate decisive mechanistic data, investigators can introduce defined CIN lesions into highly purified, senescence free donor MSCs, then monitor CIN dynamics, surface antigen expression and senescence trajectories longitudinally with single cell multiomics. In parallel, comprehensive mapping of the senescence asscociated CIN interactome, encompassing DNA repair, spindle assembly, mitophagy and innate immune pathways, should reveal biomarkers and druggable nodes that either suppress CIN driven senescence or exploit the particular vulnerabilities of senescent, genomically unstable stroma.

MSCs in HMs are not passive bystanders: they harbor a high frequency, nonclonal CIN signature that is rare in healthy donors. Mouse studies show that a single stromal lesion can initiate malignancy, while malignant HCs can impose CIN on the niche, placing MSC CIN on a spectrum from initiator to amplifier. Emerging single cell and interphase genomics eliminate earlier blind spots and demand that investigators report NCCA rates, molecular and phenotypic changes classical karyotypes. Systematic, longitudinal multiomics of paired MSCs and HCs, coupled with targeted CIN perturbations, will clarify causality and reveal actionable BMM vulnerabilities. Therapies that neutralize or exploit MSC-centered CIN therefore hold promise for overcoming microenvironment-driven resistance and improving patient outcomes.

Key research priorities are to establish whether MSC CIN ignites, sustains or merely shadows leukemogenesis in large, prospectively sampled cohorts; to define how genomically unstable MSCs remodel metabolism, cytokine output, immunomodulation and drug resistance; and to translate CIN metrics and their upstream drivers into biomarkers for patient stratification and therapeutic targeting.

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Authors and Affiliations

1. Core for Cell Technology, School of Medicine and Life Sciences, Pontifícia Universidade Católica do Paraná—PUCPR, Curitiba, 80215-901, Brazil

   Mateus de Oliveira Lisboa, Letícia Fracaro & Paulo Roberto Slud Brofman

2. Complexo Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, 80060-240, Brazil

   Tamara Borgonovo

3. Department of Physiology and Pathophysiology, University of Manitoba, Paul Albrechtsen Research Institute, Winnipeg, MB, R3E 0V9, Canada

   Aline Rangel Pozzo & Sabine Mai

Contributions

Mateus de Oliveira Lisboa (MdOL): Conceptualization, Writing – Original Draft Preparation. He was the lead writer of the manuscript, developed the overall structure of the review, synthesized the literature, and prepared the initial draft. Tamara Borgonovo (TB), Letícia Fracaro (LF), Aline Rangel-Pozzo (ARP), Paulo Roberto Slud Brofman (PRSB), and Sabine Mai (SM): Writing – Review & Editing. They contributed significantly to the manuscript by critically reviewing and revising it for important intellectual content, enhancing its clarity and coherence. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Mateus de Oliveira Lisboa or Sabine Mai.

Competing interests

The authors declare no competing interests.

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