Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis

Rambaldi, Benedetta; Diral, Elisa; Donsante, Samantha; Marzo, Noemi Di; Mottadelli, Federica; Cardinale, Lucia; Dander, Erica; Isimbaldi, Giuseppe; Pioltelli, Pietro; Biondi, Andrea; Riminucci, Mara; D’Amico, Giovanna; Elli, Elena Maria; Pievani, Alice; Serafini, Marta

doi:10.1007/s00277-020-04306-w

Cited by 6 publications

(6 citation statements)

References 49 publications

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“… 16 , 17 Regarding myeloid diseases, the most striking evidence of BM niche alteration in patients is the BM fibrosis that occurs during the development of MPN, especially in myelofibrosis (MF). Although intrinsic MSC alterations have been observed in MF patients, 18 , 19 pathological HSCs play a pivotal role in subverting the BM niche. 20 This concept is reinforced by data from patients that recovered after HCT where a complete response is defined by the complete regression of BM fibrosis.…”

Section: Alterations Of Bm Niche In Myeloid Malignancies: Clinical Ev...mentioning

confidence: 99%

A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies

Tomasoni¹,

Pievani²,

Rambaldi

et al. 2023

HemaSphere

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Until a few years ago, the onset of acute myeloid leukemia (AML) was entirely ascribed to genetic lesions in hematopoietic stem cells. These mutations generate leukemic stem cells, which are known to be the main ones responsible for chemoresistance and relapse. However, in the last years, increasing evidence demonstrated that dynamic interplay between leukemic cells and bone marrow (BM) niche is of paramount relevance in the pathogenesis of myeloid malignancies, including AML. Specifically, BM stromal niche components, such as mesenchymal stromal cells (MSCs) and their osteoblastic cell derivatives, play a key role not only in supporting normal hematopoiesis but also in the manifestation and progression of myeloid malignancies. Here, we reviewed recent clinical and experimental findings about how genetic and functional alterations in MSCs and osteolineage progeny can contribute to leukemogenesis and how leukemic cells in turn generate a corrupted niche able to support myeloid neoplasms. Moreover, we discussed how the newest single-cell technologies may help dissect the interactions between BM stromal cells and malignant hematopoiesis. The deep comprehension of the tangled relationship between stroma and AML blasts and their modulation during disease progression may have a valuable impact on the development of new microenvironment-directed therapeutic strategies, potentially useful for a wide cohort of patients.

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Section: Alterations Of Bm Niche In Myeloid Malignancies: Clinical Ev...mentioning

confidence: 99%

A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies

Tomasoni¹,

Pievani²,

Rambaldi

et al. 2023

HemaSphere

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“…Nevertheless, Ph-MPNs show a different clinical presentation and outcome [119]. PMF is defined by unique clinical features such as BM fibrosis, osteosclerosis, neo-angiogenesis, and extramedullary hematopoiesis which characterize the natural history of PMF patients, significantly affecting quality of life and life expectancy [120]. Similar to MDS-MSCs, stromal cells from CML and higherfibrosis PMF patients display functional alterations, including low proliferative potential and precocious senescence [121,122].…”

Section: Role Of Mscs In Myeloproliferative Neoplasmsmentioning

confidence: 99%

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

Giallongo,

Duminuco,

Dulcamare

et al. 2023

Biomolecules

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Mesenchymal stromal cells (MSCs) are a subset of heterogeneous, non-hematopoietic fibroblast-like cells which play important roles in tissue repair, inflammation, and immune modulation. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in recent years as key regulators of the tumor microenvironment. Indeed, they are now considered active players in the pathophysiology of hematologic malignancies rather than passive bystanders in the hematopoietic microenvironment. Once a malignant event occurs, the BMME acquires cellular, molecular, and epigenetic abnormalities affecting tumor growth and progression. In this context, MSC behavior is affected by signals coming from cancer cells. Furthermore, it has been shown that stromal cells themselves play a major role in several hematological malignancies’ pathogenesis. This bidirectional crosstalk creates a functional tumor niche unit wherein tumor cells acquire a selective advantage over their normal counterparts and are protected from drug treatment. It is therefore of critical importance to unveil the underlying mechanisms which activate a protumor phenotype of MSCs for defining the unmasked vulnerabilities of hematological cancer cells which could be pharmacologically exploited to disrupt tumor/MSC coupling. The present review focuses on the current knowledge about MSC dysfunction mechanisms in the BMME of hematological cancers, sustaining tumor growth, immune escape, and cancer progression.

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“…In fact, MSCs secrete a wide range of soluble factors (VEGFA, CXCL12, ILs) to support regenerative processes and perform immunomodulatory properties on NK cells, lymphocytes and macrophages (57). For example, Activin A, a cytokine involved in inflammation and erythropoiesis, has been reported to induce high grade marrow fibrosis in some MPN patients (8). Another example is provided by secretion of TNF-a, IL-10, and TGF-b, known to reduce the number and function of anti-leukemic cytotoxic T lymphocytes.…”

Section: A Role For Mscs In Mpnmentioning

confidence: 99%

“…On this basis, sinusoidal, arteriolar and endosteal niches appear to be distinguished not only by their specific location, but also by their unique cellular composition and molecular requirements. Moreover, increasing evidence demonstrate that alterations at different levels in the niche composition are associated with malignancies including myelodysplastic syndromes (MDS) (7) and myeloproliferative neoplasms (MPN) (8), with an additional effect on the osteo-haematopoietic niche deriving from medical treatments (9,10). Remarkable efforts have been devoted also to translating this basic knowledge, mainly derived from murine models, into the development of relevant in vitro platforms to study the human counterpart and to test drugs in a patientspecific setting (11,12).…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Niches and Tumour Cells: Lights and Shadows of a Mutual Relationship

et al. 2022

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The bone marrow (BM) niche is the spatial structure within the intra-trabecular spaces of spongious bones and of the cavity of long bones where adult haematopoietic stem cells (HSCs) maintain their undifferentiated and cellular self-renewal state through the intervention of vascular and nervous networks, metabolic pathways, transcriptional and epigenetic regulators, and humoral signals. Within the niche, HSCs interact with various cell types such as osteoblasts, endothelial cells, macrophages, and mesenchymal stromal cells (MSCs), which maintain HSCs in a quiescent state or sustain their proliferation, differentiation, and trafficking, depending on body needs. In physiological conditions, the BM niche permits the daily production of all the blood and immune cells and their admittance/ingress/progression into the bloodstream. However, disruption of this delicate microenvironment promotes the initiation and progression of malignancies such as those included in the spectrum of myeloid neoplasms, also favouring resistance to pharmacological therapies. Alterations in the MSC population and in the crosstalk with HSCs owing to tumour-derived factors contribute to the formation of a malignant niche. On the other hand, cells of the BM microenvironment cooperate in creating a unique milieu favouring metastasization of distant tumours into the bone. In this framework, the pro-tumorigenic role of MSCs is well-documented, and few evidence suggest also an anti-tumorigenic effect. Here we will review recent advances regarding the BM niche composition and functionality in normal and in malignant conditions, as well as the therapeutic implications of the interplay between its diverse cellular components and malignant cells.

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Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis

Cited by 6 publications

References 49 publications

A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies

A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers

Bone Marrow Niches and Tumour Cells: Lights and Shadows of a Mutual Relationship

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