Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes

Falconi, Giulia; Fabiani, Emiliano; Fianchi, Luana; Criscuolo, Marianna; Raffaelli, Chiara Spertilli; Bellesi, Silvia; Hohaus, Stefan; Voso, Maria Teresa; D’Alo’, Francesco; Leone, Giuseppe

doi:10.1016/j.exphem.2015.10.005

Cited by 35 publications

(42 citation statements)

References 30 publications

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“…Mesenchymal stromal cell function can be assessed in vitro based on morphology, differentiation capacity, proliferative capacity, and ability to support co-cultured HSPCs. In terms of morphology, investigators have observed MDS-derived mesenchymal stromal cells to be disorganized in appearance compared to the fibroblastic-like morphology of normal donor-derived mesenchymal stromal cells [28–30]. However, several other groups reported no changes in the morphology of MDS-derived mesenchymal stromal compared to normal controls [31–36].…”

Section: In Vitro Evidence For Stromal Abnormalities In Mdsmentioning

confidence: 99%

“…The investigators attributed defective proliferation to increased non-canonical WNT signaling, implicated in inhibition of mesenchymal stem/progenitor cell proliferation, based on supportive transcriptional data [41]. This was accompanied by decreased gene expression of canonical WNT signaling pathway components and downstream transcriptional targets, suggesting that aberrancies in WNT signaling may explain the diminished proliferative capacity [30, 41]. Furthermore, increased cell death may also contribute to growth impairment as MDS-derived stromal cultures have decreased live cells [40] and increased TUNEL-positive apoptotic cells [34].…”

Section: In Vitro Evidence For Stromal Abnormalities In Mdsmentioning

confidence: 99%

“…Furthermore, increased cell death may also contribute to growth impairment as MDS-derived stromal cultures have decreased live cells [40] and increased TUNEL-positive apoptotic cells [34]. Consistent with a diminished proliferative capacity, multiple groups report that MDS-derived mesenchymal stromal cells have reduced clonogenic potential evidenced by the production of fewer fibroblastic colony-forming units (CFU-F) in vitro [28–30, 40, 42]. While two studies found no differences in the growth properties of MDS-derived mesenchymal stromal cells, they did identify other functional alterations such as an impaired capacity to support HSPCs in vitro [32, 45].…”

Section: In Vitro Evidence For Stromal Abnormalities In Mdsmentioning

confidence: 99%

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The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Calvi

2017

Experimental Hematology

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Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem and progenitor cells and represent the most common cause of acquired marrow failure. Hallmarked by ineffective hematopoiesis, dysplastic marrow, and risk of transformation to acute leukemia, MDS remains a poorly treated disease. Although identification of hematopoietic aberrations in human MDS has contributed significantly to our understanding of MDS pathogenesis, evidence now identify the bone marrow microenvironment (BMME) as another key contributor to disease initiation and progression. With improved understanding of the BMME, we are beginning to refine the role of the hematopoietic niche in MDS. Despite genetic diversity in MDS, interaction between MDS and the BMME appears to be a common disease feature, and therefore represents an appealing therapeutic target. Further understanding of the interdependent relationship between MDS and its niche is needed to delineate the mechanisms underlying hematopoietic failure and how the microenvironment can be clinically targeted. This review will provide an overview of data from human MDS and murine models supporting a role for BMME dysfunction at several steps of disease pathogenesis. While no models or human studies so far have combined all these findings, we will review current data identifying BMME involvement in each step of MDS pathogenesis, organized to reflect the chronology of BMME contribution as the normal hematopoietic system becomes myelodysplastic and MDS progresses to marrow failure and transformation. Although microenvironmental heterogeneity and dysfunction certainly add complexity to this syndrome, data are already demonstrating that targeting microenvironmental signals may represent novel therapeutic strategies for MDS treatment.

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Section: In Vitro Evidence For Stromal Abnormalities In Mdsmentioning

confidence: 99%

Section: In Vitro Evidence For Stromal Abnormalities In Mdsmentioning

confidence: 99%

Section: In Vitro Evidence For Stromal Abnormalities In Mdsmentioning

confidence: 99%

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The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Calvi

2017

Experimental Hematology

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“…On the other hand, exposure of normal BMSCs to MDS renders them malignant-like, which highlights MDS-induced BMSC reprogramming. 83 Alterations of WNT signaling in BMSCs have been associated with defective BMSC proliferation in MDS, 84,85 partially because of the induction of senescence. 86 Communication between BMSCs and MDS cells is partly mediated by extracellular vesicles.…”

Section: Role Of Bmscsmentioning

confidence: 99%

“…[84][85][86] Increased osteogenic potential of BMSCs 110 p53-S100A8/9-TLR inflammatory signaling in BMSCs causes genotoxic stress in HSCs and supports MDS development. 78 PTH, parathyroid hormone; TLR, toll-like receptor.…”

mentioning

confidence: 99%

Myeloid malignancies and the microenvironment

Korn

Méndez-Ferrer

2017

Blood

136

106

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Research in the last few years has revealed a sophisticated interaction network between multiple bone marrow cells that regulate different hematopoietic stem cell (HSC) properties such as proliferation, differentiation, localization, and self-renewal during homeostasis. These mechanisms are essential to keep the physiological HSC numbers in check and interfere with malignant progression. In addition to the identification of multiple mutations and chromosomal aberrations driving the progression of myeloid malignancies, alterations in the niche compartment recently gained attention for contributing to disease progression. Leukemic cells can remodel the niche into a permissive environment favoring leukemic stem cell expansion over normal HSC maintenance, and evidence is accumulating that certain niche alterations can even induce leukemic transformation. Relapse after chemotherapy is still a major challenge during treatment of myeloid malignancies, and cure is only rarely achieved. Recent progress in understanding the niche-imposed chemoresistance mechanisms will likely contribute to the improvement of current therapeutic strategies. This article discusses the role of different niche cells and their stage- and disease-specific roles during progression of myeloid malignancies and in response to chemotherapy.

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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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Impairment of PI3K/AKT and WNT/β-catenin pathways in bone marrow mesenchymal stem cells isolated from patients with myelodysplastic syndromes

Cited by 35 publications

References 30 publications

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

Myeloid malignancies and the microenvironment

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

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