MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

Hayashi, Yasutaka; Kawabata, Kimihito C.; Tanaka, Yosuke; Uehara, Yasufumi; Mabuchi, Yo; Murakami, Koichi; Nishiyama, Akira; Kiryu, Shigeru; Yoshioka, Yusuke; Ota, Yasunori; Sugiyama, Tatsuki; Mikami, K.; Tamura, Moe; Asada, Shuhei; Takeda, Reina; Kunisaki, Yuya; Yokoyama, Kazuaki; Uchida, Tatsuo; Hagihara, Masao; Ohno, Nobuhiro; Usuki, Kensuke; Tojo, Arinobu; Katayama, Yoshio; Goyama, Susumu; Arai, Fumio; Tamura, Tomohide; Nagasawa, Takashi; Ochiya, Takahiro; Inoue, Daichi; Kitamura, Toshio

doi:10.1016/j.celrep.2022.110805

Cited by 14 publications

(11 citation statements)

References 98 publications

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“…Notably, neutralization of the increased serum levels of fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis and bone mineralization and an inhibitor of erythropoiesis, restored bone microarchitecture and improved osteoid mineralization and anemia (61). Elevated FGF23 levels and increased amount of non mineralized bone were also observed in samples from MDS patients, thereby corroborating the findings in NHD13 mice (61) Impaired bone metabolism was also reported recently in the Abcg2 MDS/AML mouse model (62). In this model, expression of a mutant enhancer of zeste homolog 2 (EZH2-the catalytic subunit of polycomp repressive complex 2, one of the 10 most frequently mutated genes in MDS ( 63)) lacking the catalytic SET domain (EZH2-dSET) induces Abcg2 (a drug efflux transporter) upregulation.…”

Section: Evidence For Deregulations Of the Bm Mesenchymal Compartment...supporting

confidence: 75%

“…Impaired bone metabolism was also reported recently in the Abcg2 MDS/AML mouse model ( 62 ). In this model, expression of a mutant enhancer of zeste homolog 2 (EZH2-the catalytic subunit of polycomp repressive complex 2, one of the 10 most frequently mutated genes in MDS ( 63 )) lacking the catalytic SET domain (EZH2-dSET) induces Abcg2 (a drug efflux transporter) up-regulation.…”

Section: Properties Of Ex Vivo Expanded Mds-derive...supporting

confidence: 72%

“…Furthermore, the authors demonstrated that murine MDS/AML cells inhibited the commitment of BM-MSCs towards osteoprogenitors, thereby deregulating the capacity of MSCs to support normal hematopoiesis. This suppression was mediated via extracellular vesicles derived from MDS/AML cells ( 62 ). Collectively, this data add to the established notion that malignant hematopoietic cells are able to modify MSCs, so that the latter promote disease propagation and evolution.…”

Section: Properties Of Ex Vivo Expanded Mds-derive...mentioning

confidence: 99%

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The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

2023

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Myelodysplastic syndromes include a broad spectrum of malignant myeloid disorders that are characterized by dysplastic ineffective hematopoiesis, reduced peripheral blood cells counts and a high risk of progression to acute myeloid leukemia. The disease arises primarily because of accumulating chromosomal, genetic and epigenetic changes as well as immune-mediated alterations of the hematopoietic stem cells (HSCs). However, mounting evidence suggests that aberrations within the bone marrow microenvironment critically contribute to myelodysplastic syndrome (MDS) initiation and evolution by providing permissive cues that enable the abnormal HSCs to grow and eventually establish and propagate the disease. Mesenchymal stromal cells (MSCs) are crucial elements of the bone marrow microenvironment that play a key role in the regulation of HSCs by providing appropriate signals via soluble factors and cell contact interactions. Given their hematopoiesis supporting capacity, it has been reasonable to investigate MSCs’ potential involvement in MDS. This review discusses this issue by summarizing existing findings obtained by in vitro studies and murine disease models of MDS. Furthermore, the theoretical background of targeting the BM-MSCs in MDS is outlined and available therapeutic modalities are described.

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Section: Evidence For Deregulations Of the Bm Mesenchymal Compartment...supporting

confidence: 75%

Section: Properties Of Ex Vivo Expanded Mds-derive...supporting

confidence: 72%

Section: Properties Of Ex Vivo Expanded Mds-derive...mentioning

confidence: 99%

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The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

2023

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“…It has been well described that MDS cells induce specific alterations in the BM microenvironment [ 110 , 111 ] transforming it to an “MDS-promoting” niche that in turn supports the growth and proliferation of malignant cells via the secretion of cytokines, growth factors and modulation of immune response [ 5 , 6 , 112 , 113 , 114 ] while suppressing normal hematopoiesis [ 111 ]. Similarly, MDS cells overexpress various cytokine receptors and co-receptors that mediate the activity of cytokines secreted by BM stromal cells, promoting the growth and suppressing the differentiation of malignant cells [ 115 , 116 ].…”

Section: Extracellular Vesiclesmentioning

confidence: 99%

“…Thus, it is possible that MDS-derived EVs may affect other cells in the BM micro-environment. Indeed, it was recently demonstrated that MDS-derived EVs suppress the osteo-lineage differentiation of mesenchymal stromal cells, which impairs their ability to support healthy hematopoietic stem cells (HSC) [ 111 ]. Further analysis of the effect of MDS-derived EVs in the BM microenvironment cells and mechanistic studies are required to improve our understanding of their role in the interaction between MDS and BM niche.…”

Section: Extracellular Vesiclesmentioning

confidence: 99%

Extracellular Vesicles in Myeloid Neoplasms

Karantanou

Minciacchi

Karantanos

2022

IJMS

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Myeloid neoplasms arise from malignant primitive cells, which exhibit growth advantage within the bone marrow microenvironment (BMM). The interaction between these malignant cells and BMM cells is critical for the progression of these diseases. Extracellular vesicles (EVs) are lipid bound vesicles secreted into the extracellular space and involved in intercellular communication. Recent studies have described RNA and protein alterations in EVs isolated from myeloid neoplasm patients compared to healthy controls. The altered expression of various micro-RNAs is the best-described feature of EVs of these patients. Some of these micro-RNAs induce growth-related pathways such as AKT/mTOR and promote the acquisition of stem cell-like features by malignant cells. Another well-described characteristic of EVs in myeloid neoplasms is their ability to suppress healthy hematopoiesis either via direct effect on healthy CD34+ cells or via alteration of the differentiation of BMM cells. These results support a role of EVs in the pathogenesis of myeloid neoplasms. mainly through mediating the interaction between malignant and BMM cells, and warrant further study to better understand their biology. In this review, we describe the reported alterations of EV composition in myeloid neoplasms and the recent discoveries supporting their involvement in the development and progression of these diseases.

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Immune‐monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium

Tentori,

Zhao,

Tinterri

et al. 2024

HemaSphere

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Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

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MDS cells impair osteolineage differentiation of MSCs via extracellular vesicles to suppress normal hematopoiesis

Cited by 14 publications

References 98 publications

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

The mesenchymal compartment in myelodysplastic syndrome: Its role in the pathogenesis of the disorder and its therapeutic targeting

Extracellular Vesicles in Myeloid Neoplasms

Immune‐monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium

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