The Role of Notch and Wnt Signaling in MSC Communication in Normal and Leukemic Bone Marrow Niche

Notch and Wnt signaling are highly conserved intercellular communication pathways involved in developmental processes, such as hematopoiesis. Even though data from literature support a role for these two pathways in both physiological hematopoiesis and leukemia, there are still many controversies concerning the nature of their contribution. Early studies, strengthened by findings from T-cell acute lymphoblastic leukemia (T-ALL), have focused their investigation on the mutations in genes encoding for components of the pathways, with limited results except for B-cell chronic lymphocytic leukemia (CLL); in because in other leukemia the two pathways could be hyper-expressed without genetic abnormalities. As normal and malignant hematopoiesis require close and complex interactions between hematopoietic cells and specialized bone marrow (BM) niche cells, recent studies have focused on the role of Notch and Wnt signaling in the context of normal crosstalk between hematopoietic/leukemia cells and stromal components. Amongst the latter, mesenchymal stromal/stem cells (MSCs) play a pivotal role as multipotent non-hematopoietic cells capable of giving rise to most of the BM niche stromal cells, including fibroblasts, adipocytes, and osteocytes. Indeed, MSCs express and secrete a broad pattern of bioactive molecules, including Notch and Wnt molecules, that support all the phases of the hematopoiesis, including self-renewal, proliferation and differentiation. Herein, we provide an overview on recent advances on the contribution of MSC-derived Notch and Wnt signaling to hematopoiesis and leukemia development.

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Sipa1 deficiency–induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm

Blood Advances ◽

10.1182/bloodadvances.2017013599 ◽

2018 ◽

Vol 2 (5) ◽

pp. 534-548 ◽

Cited By ~ 15

Author(s):

Pingnan Xiao ◽

Monika Dolinska ◽

Lakshmi Sandhow ◽

Makoto Kondo ◽

Anne-Sofie Johansson ◽

...

Keyword(s):

Bone Marrow ◽

Myeloproliferative Neoplasm ◽

Hematopoietic Cells ◽

Bone Marrow Niche ◽

Bm Niche ◽

Key Points

Key Points Sipa1 loss leads to BM niche alterations prior to the initiation of MPN. Sipa1-deficient BM niche induces lethal MPN from normal hematopoietic cells.

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Cathepsin B Mediated Lysosomal Degradation in Macrophages Controls the Pharmacokinetics of the Therapeutic Protein Asparaginase

Blood ◽

10.1182/blood.v126.23.3768.3768 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3768-3768

Author(s):

Laurens T Van Der Meer ◽

Samantha YA Terry ◽

Dorette van Ingen Schenau ◽

Kiki Andree ◽

Gerben M Franssen ◽

...

Keyword(s):

Bone Marrow ◽

In Vivo Imaging ◽

Cathepsin B ◽

Rational Design ◽

Lymphoblastic Leukemia ◽

Therapeutic Protein ◽

Bone Marrow Niche ◽

Lysosomal Protease

Abstract Asparaginase (ASNase) is one of the cornerstones of the multi-drug treatment protocol that is used to treat acute lymphoblastic leukemia (ALL) in pediatric and adult patients. Despite the fact that ASNase has been used in ALL treatment protocols for decades, little is known about the biodistribution and the mechanism of ASNase turnover in vivo. A large inter-individual variation in ASNase pharmacokinetics is observed in patients. While elevated ASNase levels are associated with an increase in adverse events, underexposure, frequently caused by antibody mediated clearance, seriously reduces therapeutic efficacy. To date, it is not possible to predict pharmacokinetics of ASNase in individual patients and therefore current therapeutic protocols are supported by frequent monitoring of ASNase levels and adjustments of administration schemes. We used an in vivo imaging approach to study ASNase biodistribution and pharmacodynamics in a mouse model and provide in vitro and in vivo evidence that identifies the endo-lysosomal protease Cathepsin B in macrophages as a critical component of ASNase degradation. Results/Discussion Mice were injected with 111Indium-labeled ASNase and biodistribution was monitored by quantitative microSPECT/CT scans and ex vivo analysis of organs using a gamma counter. Over time, ASNase accumulated in the liver and particularly the spleen and the bone marrow. We hypothesized that macrophages in these organs, efficiently take up the ASNase, thereby rapidly clearing the active enzyme from the blood. Immunohistochemical analysis confirmed the presence of ASNase in cells positive for the murine macrophage marker F4/80. To confirm the importance of macrophage populations in ASNase clearance, we depleted mice from phagocytic cells by injection of clodronate liposomes, and studied ASNase biodistribution and kinetics. Indeed, clodronate pretreatment significantly diminished the accumulation of ASNase in the liver, spleen and the bone marrow while doubling the circulatory half-life of serum ASNase activity. We conclude from these experiments that macrophages determine the pharmacokinetics of asparaginase, which raises the question whether rapid clearance of the drug by bone marrow resident macrophages will negatively affect the depletion of asparagine in the bone marrow niche. We previously linked a germline mutation in the gene encoding endosomal protease Cathepsin B to strongly diminished asparaginase degradation in a pediatric ALL patient. To connect the macrophage mediated clearance to the proposed role of Cathepsin B in ASNase degradation, we studied the contribution of this protease in macrophage-mediated degradation of asparaginase. We used cell lines to show that Cathepsin B expression is induced during differentiation from monocytes towards macrophages. This is consistent with our finding that macrophages, but not monocytes, are capable of degrading ASNase. Furthermore, we used both chemical inhibition and RNAi mediated knockdown of Cathepsin B to show that this protease is required for ASNase degradation in these macrophages. Finally, by comparing Cathepsin B knockout mice with wildtype littermates, we demonstrated that loss of Cathepsin B activity significantly delayed clearance of serum asparaginase, consistent with a prominent role for this lysosomal protease in ASNase turnover. In conclusion, by using in vivo imaging we showed that asparaginase is efficiently cleared from the circulation by macrophages. In particular, bone marrow resident macrophages may provide a protective environment for leukemic cells by effectively removing the therapeutic protein from the bone marrow niche. However, both the prominent role of macrophages and the importance of the lysosomal protease Cathepsin B in asparaginase clearance, may allow the rational design of a next generation asparaginase. Disclosures Metselaar: Enceladus Pharmaceuticals: Employment, Equity Ownership.

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Modeling the human bone marrow niche in mice: From host bone marrow engraftment to bioengineering approaches

Journal of Experimental Medicine ◽

10.1084/jem.20172139 ◽

2018 ◽

Vol 215 (3) ◽

pp. 729-743 ◽

Cited By ~ 36

Author(s):

Ander Abarrategi ◽

Syed A. Mian ◽

Diana Passaro ◽

Kevin Rouault-Pierre ◽

William Grey ◽

...

Keyword(s):

Bone Marrow ◽

Mouse Models ◽

Hematopoietic Cells ◽

Human Growth ◽

Human Bone ◽

Human Bone Marrow ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Bm Niche ◽

Stem And Progenitor Cells

Xenotransplantation of patient-derived samples in mouse models has been instrumental in depicting the role of hematopoietic stem and progenitor cells in the establishment as well as progression of hematological malignancies. The foundations for this field of research have been based on the development of immunodeficient mouse models, which provide normal and malignant human hematopoietic cells with a supportive microenvironment. Immunosuppressed and genetically modified mice expressing human growth factors were key milestones in patient-derived xenograft (PDX) models, highlighting the importance of developing humanized microenvironments. The latest major improvement has been the use of human bone marrow (BM) niche–forming cells to generate human–mouse chimeric BM tissues in PDXs, which can shed light on the interactions between human stroma and hematopoietic cells. Here, we summarize the methods used for human hematopoietic cell xenotransplantation and their milestones and review the latest approaches in generating humanized BM tissues in mice to study human normal and malignant hematopoiesis.

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Role of Cell Adhesion in the Maintenance of Hematopoietic Stem Cells in the Bone Marrow Niche.

Blood ◽

10.1182/blood.v104.11.669.669 ◽

2004 ◽

Vol 104 (11) ◽

pp. 669-669

Author(s):

Fumio Arai ◽

Atsushi Hirao ◽

Kentaroh Hosokawa ◽

Toshio Suda

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Cell Adhesion ◽

Side Population ◽

Bone Marrow Niche ◽

Bone Surface ◽

Hematopoietic Stem ◽

Bm Niche

Abstract Interaction of HSCs with their particular microenvironments, known as the stem cell niches, is critical for adult hematopoiesis in the bone marrow (BM). HSCs are keeping the balance of the quiescence and the self-renewal in the stem cell niche, and are maintaining long-term hematopoiesis. We have demonstrated that HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and anti-apoptotic, transplantable and comprise a side-population (SP) of HSCs, which contact closely to angiopoietin-1, a ligand for Tie2, expressing osteoblasts (OBs) in the BM niche. Tie2 and Ang-1 are part of a key signaling interaction between HSCs and niche cells. This signaling pathway regulates the feature of HSCs in the BM niche. The interaction of Tie2 with Ang-1 in vitro is sufficient to maintain the long-term blood-repopulating (LTR) activity of HSCs in vivo by preventing cell division. In addition, Ang-1 enhanced the ability of HSCs to become quiescent and also induced their adhesion to bone surface, resulting protection of HSC compartment from stresses which suppress hematopoiesis (Arai et al., Cell, 2004). In this study, we focused on the role of cell adhesion molecule on the maintenance of HSCs in BM niche. A previous paper reported that both quiescent HSCs and some of osteoblasts express N-cadherin. We found that Tie2+ HSC expressed N- and VE-cadherin, and OBs expressed N-, P-, and OB-cadherin. This suggests that an adherens junction between HSCs and OBs created via N-cadherin may contribute to HSC maintenance. Furthermore, N-cadherin overexpressing OP9 stromal cells (OP9/N-cadherin) maintained LTC-IC more than control OP9 cells did. Overexpression of N-cadherin in HSCs also maintained colony formation. In addition, in the presence of Ang-1 in coculture of OP9/N-cadherin and HSCs facilitated the maintenance of CFU-C and HPP-CFC formation after long-term culture. Furthermore, Ang-1 treatment upregulated the expression of N-cadherin in Tie2+ HSCs as well as β1-integrin. It suggests that Tie2/Ang-1 signaling enhanced cell-cell adhesion between HSCs and OBs. Altogether, these observations led us to the novel model that the localization of HSCs on bone surface is regulated by stem cell specific adhesion molecules such as N-cadherin. Once the HSCs adjacently localize to OBs, Ang-1 produced by OBs may activate Tie2 on the HSCs and promote tight adhesion of HSCs in the niche, resulting in quiescence and enhanced survival of HSCs.

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Deletion of mouseSetd4promotes the recovery of hematopoietic failure

10.1101/860239 ◽

2019 ◽

Author(s):

Xing Feng ◽

Huimei Lu ◽

Jingyin Yue ◽

Megha Shettigar ◽

Jingmei Liu ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Whole Body ◽

List Type ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Adult Mice ◽

Bm Niche ◽

Deficient Mice

AbstractAcquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducingSetd4deletion in adult mice, we found that loss ofSetd4improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of theSetd4deficient HSC, but thatSetd4deficient HSC were actually more sensitive to radiation. However, theSetd4deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis inSetd4deficient mice. These findings not only revealed a previously unrecognized role of theSetd4as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicatedSetd4as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation.Key pointsDeletion ofSetd4in adult mice improved the survival from hematopoietic failure.Setd4deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.

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Novel Role of Plasmin in Mobilization and of uPAR in Retention of Hematopoietic Stem/Progenitor Cells in the Bone Marrow Niche: Therapeutic Implications.

Blood ◽

10.1182/blood.v104.11.117.117 ◽

2004 ◽

Vol 104 (11) ◽

pp. 117-117

Author(s):

Marc Tjwa ◽

Nicolai Sidenius ◽

Koen Theunissen ◽

Rute Moura ◽

Lieve Moons ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Soluble Form ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Hematopoietic Recovery ◽

Bm Niche ◽

Retention Signal ◽

Pai 1

Abstract Hematopoietic stem/progenitor cells (HSC/HPCs) are retained in the bone marrow (BM) niche via receptor-ligand interactions and mobilized from the BM after proteolytic degradation of these retention complexes. Yet, the proteinases and retention signals involved remain incompletely identified. Here, we studied the role of the plasminogen proteinase system with its plasminogen activators PA) tPA and uPA, and active plasmin (Pli) in chemo- and G-CSF-induced mobilization of HPCs and HSCs. Therefore, 5-fluorouracil (5-FU) or G-CSF were administered to mice lacking plasminogen (Plg−/−), tPA (tPA−/−), uPA (uPA−/−), both activators (tPA−/−uPA−/−), uPAR (uPAR−/−), PAI-1 (PAI-1−/−), or α2-antiplasmin (α2-AP−/−). 5-FU treatment in WT mice elevated Pli activity in BM plasma 5-fold, killed 10% of WT mice, and increased number/proliferation of HSC/HPCs in the surviving mice, with full hematopoietic recovery after 3 weeks. In contrast, up to 75% of 5-FU-treated Plg−/−and tPA−/−uPA−/− demised in the early phase of recovery, with reduced number/proliferation of HSC/HPCs and delayed hematopoietic recovery. Following G-CSF, deficiency of Plg or inhibition of Pli by tranexamic acid reduced HPC expansion and HSC translocation in the BM, resulting in impaired HPC/HSC mobilization, by up to 55% and 75%, respectively. Further analysis using uPA−/− and tPA−/− mice revealed that uPA was critical for 5-FU-induced mobilization, whereas tPA was crucial for G-CSF-induced mobilization. In addition, analysis of mice lacking MMP-2, -3, -9, and -12 revealed that 5-FU- and G-CSF-induced mobilization required predominantly MMP-9 and -3, respectively. MMP-3 and MMP-9 activities upon mobilization were reduced in Plg−/− mice, suggesting that Pli activates these MMPs. In the absence of Plg, degradation of fibronectin in the BM and production of soluble Kit ligand (but not SDF1 α) were impaired, indicating additional downstream targets of Pli. uPAR is a membrane-anchored receptor for uPA, which is cleaved into a soluble form (suPAR) by Pli and other proteinases. Interestingly, uPAR was expressed on BM-derived HPC/HSCs, and uPAR deficiency reduced their retention within the BM niche in vitro and in vivo. Furthermore, uPAR−/− mice showed poor HSC/HPC mobilization in response to 5-FU and G-CSF, while suPAR administration in WT mice amplified G-CSF-induced mobilization. Moreover, suPAR levels in the BM were increased in WT but not in Plg−/− mice during mobilization, indicating, all together, that uPAR might be a novel retention signal for HSC/HPCs in the BM niche. Finally, increased Pli activity in PAI-1−/− and α2-AP−/− mice, and WT mice treated with tenecteplase (i.e. recombinant tPA variant used for clinical thrombolysis) enhanced G-CSF-induced mobilization. Importantly, initial results suggest that thrombolytic treatment of individuals after acute myocardial infarction also seemed to stimulate HPC mobilization, extrapolating our findings to man. In conclusion, these genetic and pharmacological data reveal, for the first time, a novel role for uPAR as a retention signal for HSC/HPCs in the BM and suggest that strategies to increase PA or Pli activity might offer novel therapeutic opportunities for HSC/HPC mobilization.

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Embigin Regulates HSPC Homing and Quiescence and Acts As a Cell Surface Marker for a Niche Factor-Enriched Subset of Osteolineage Cells

Blood ◽

10.1182/blood.v126.23.663.663 ◽

2015 ◽

Vol 126 (23) ◽

pp. 663-663 ◽

Cited By ~ 1

Author(s):

Lev Silberstein ◽

Peter V. Kharchenko ◽

Youmna Sami Kfoury ◽

Francois Mercier ◽

Raphael Turcotte ◽

...

Keyword(s):

Bone Marrow ◽

Cell Surface ◽

Functional Role ◽

Hematopoietic Cells ◽

Surface Marker ◽

Bone Marrow Niche ◽

A Cell ◽

Niche Factor ◽

Osteolineage Cells

Abstract Background. Discovery of niche-derived HSPC regulators is critical for further development of novel therapeutic approaches to promote HSPC regeneration. We have previously reported a proximity-based approach to the study of the bone marrow niche, which is based on the transcriptional comparison of osteolineage cells (OLCs) located close (proximal OLCs) or further away from transplanted HSPC (Blood 2014;124: 773), which lead to identification of IL18 as a quiescence regulator of early progenitors. We now report the results of functional validation for another molecule - Embigin - identified through this strategy as a hematopoietic regulator. Results. Embigin is a cell adhesion molecule with poorly characterized function. Our analysis showed that Embigin expression in proximal OLCs was significantly higher. Since the genetic tools for this molecule do not exist, we used a neutralizing antibody against Embigin to investigate the effect of Embigin blockade on primitive hematopoietic cells. We found that injection of anti-Embigin resulted in mobilization of myeloid progenitors and colony-forming cells (CFC) into the blood. In contrast, Embigin blockade was associated with a homing defect when LKS cells [known to express Embigin] were either pre-incubated with anti-Embigin antibody or injected into anti-Embigin pretreated animals, overall suggesting that Embigin regulates retention and localization of primitive hematopoietic cells in the bone marrow. Moreover, animals treated with anti-Embigin antibody had a higher frequency and proliferative activity of primitive hematopoietic cells, as demonstrated by cell cycle and BrdU incorporation studies and an increased CFC, consistent with Embigin-mediated localization also affecting HSPC cell cycling. Bone marrow from anti-Embigin treated mice reconstituted poorly when competitively transplanted with untreated animal marrow into irradiated recipients, likely due to the impaired homing and increased cell cycling. Finally, pre-treating irradiated recipients with anti-Embigin resulted in increased proliferation of transplanted WT LKS cells. Collectively, these data are consistent with Embigin serving as a regulator of HSPC localization and quiescence. Given a functional role of Embigin in the bone marrow niche and an overlapping pattern of expression with VCAM1, a known niche-derived HSPC regulator, in proximal OLCs we explored the use of Embigin in conjunction with VCAM1 as cell surface markers for prospective isolation of niche factor-enriched OLC subset by flow cytometry. Using this strategy, we were able to purify a rare OLC subset of CD45- Ter119-V CAM-1+E mbigin+ cells (termed VE cells), which were enriched for niche factor expression as compared to their non-VE counterparts. VE cells were transcriptionally distinct from other, previously defined niche subsets such as nestin-GFPdim mesenchymal stem cells, nestin-GFPbright pericytes and N-cadherin-positive osteoblastic cells. In particular, VE cells expressed higher levels of most niche factors than nestin-GFPbright cells - a cell population recently characterized as regulating HSPC quiescence. Interestingly, the expression profile of VE cells from animals transplanted with LT-HSCs and those which were irradiated but injected with saline alone demonstrated upregulation of cell adhesion molecules in the LT-HSC-injected group, suggesting that VE cells are involved in bidirectional communication within the niche. To investigate a functional role of VE cells, we performed co-culture experiments in which we compared the effect of VE and non-VE cells on HSPC proliferation and engraftment. We found that in the presence of VE cells, HSPCs proliferated at slower rate and generated a lower hematopoietic colony number, consistent with quiescence-inducing effect. Upon transplantation, VE-cultured HSPCs generated a higher level of chimerism compared to those cultured on non-VE layer, indicating a superior ability of VE cells to support engraftment and reconstitution properties of HSPC during the in vitro culture. Conclusion. Our work defines Embgin as a previously unrecognized hematopoietic regulator and a cell surface marker for a niche factor-enriched subset of the osteolineage cells which regulates HSPC quiescence. Pharmacological blockade of Embigin signaling may serve as a potential therapeutic tool to enhance hematopoietic regeneration. Disclosures No relevant conflicts of interest to declare.

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The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

International Journal of Molecular Sciences ◽

10.3390/ijms22094426 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4426

Author(s):

Erica Dander ◽

Chiara Palmi ◽

Giovanna D’Amico ◽

Giovanni Cazzaniga

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

B Cell ◽

Lymphoblastic Leukemia ◽

Leukemic Cell ◽

Leukemic Cells ◽

Bone Marrow Niche ◽

Disease Manifestation ◽

Cell Acute Lymphoblastic Leukemia

Genetic lesions predisposing to pediatric B-cell acute lymphoblastic leukemia (B-ALL) arise in utero, generating a clinically silent pre-leukemic phase. We here reviewed the role of the surrounding bone marrow (BM) microenvironment in the persistence and transformation of pre-leukemic clones into fully leukemic cells. In this context, inflammation has been highlighted as a crucial microenvironmental stimulus able to promote genetic instability, leading to the disease manifestation. Moreover, we focused on the cross-talk between the bulk of leukemic cells with the surrounding microenvironment, which creates a “corrupted” BM malignant niche, unfavorable for healthy hematopoietic precursors. In detail, several cell subsets, including stromal, endothelial cells, osteoblasts and immune cells, composing the peculiar leukemic niche, can actively interact with B-ALL blasts. Through deregulated molecular pathways they are able to influence leukemia development, survival, chemoresistance, migratory and invasive properties. The concept that the pre-leukemic and leukemic cell survival and evolution are strictly dependent both on genetic lesions and on the external signals coming from the microenvironment paves the way to a new idea of dual targeting therapeutic strategy.

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Bone marrow stromal cells from MDS and AML patients show increased adipogenic potential with reduced Delta-like-1 expression

Scientific Reports ◽

10.1038/s41598-021-85122-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marie-Theresa Weickert ◽

Judith S. Hecker ◽

Michèle C. Buck ◽

Christina Schreck ◽

Jennifer Rivière ◽

...

Keyword(s):

Bone Marrow ◽

Cell Fate ◽

Stromal Cells ◽

Adipogenic Differentiation ◽

Cell Types ◽

Bone Marrow Niche ◽

Differentiation Potential ◽

Hematopoietic Stem ◽

Bm Niche

AbstractMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73+ CD105+ CD271+ BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.

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BONE MARROW PROFILE IN HEMATOLOGICAL DISORDERS IN YEMENI PATIENS

10.36106/ijar/2316392 ◽

2021 ◽

pp. 61-65

Author(s):

Saeed Thabet Nasher ◽

Fayed Alyousufy ◽

Khaled Alkubati ◽

Sadam Al Halimy ◽

Ramia Al Athwary

Keyword(s):

Bone Marrow ◽

Visceral Leishmaniasis ◽

Lymphoblastic Leukemia ◽

Bone Marrow Examination ◽

Myeloproliferative Disorder ◽

Lymphocytic Leukemia ◽

Published Data ◽

Hematological Disorders ◽

Hematological Diseases ◽

Age Related

There is paucity of information about the prevalence of hematological disorders in Yemen and neighboring countries .This is the rst project to evaluate the relative spectrum of hematological diseases in Taiz and Ibb governorate Yemen ,by method of bone marrow examination which is considered an important valuable diagnostic tool, for evaluation and nal diagnosis of various hematological and non-hematological disorders especially when CBC and peripheral blood lm study and other investigation failed to give a diagnosis . OBJECTIVES: The aim of this study was to evaluate the spectrum of haematological diseases diagnosed by bone marrow examination in Taiz and IBB governorates Yemen between September 2016 and October 2020 .Patients and method : A total of 1108 patients aged between (1 -100 )years old were evaluated by bone marrow examination at referral hematological center in IBB city Yemen . Relevant investigations were performed when needed. After exclusion of 98 patients with normal bone marrow ndings ,a total of 1010 patients had hematological disorders , and their data were analyzed. There were 527 (52.2 %) males and 483(47.8 %) females . A total of 655(64.9%) patients had benign hematological diseases and 355 (35.1% ) patients had malignant hematological diseases . RESULTS :A total of 138 patients had Iron deciency anemia ,107 had immune thrombocytopenic purpura (ITP) , 92 had hypersplenism,84 had Acute lymphoblastic leukemia ,79 had Acute myeloid leukaemia, 71 had megaloblastic anemia 58 had myeloproliferative disorder , 53 had Chronic myeloid leukemia , 45 had hemolytic anemia ,45had visceral leishmaniasis. 44 had malaria, 38 had chronic lymphocytic leukemia 38 had anemia of chronic disease ,25 had aplastic anemia ,25 had myelodysplastic syndromes, ,21 had anemia of infection ,19 had congenital syndroms,7had multiple myeloma ,6 had mixed deciency anemia and 5 had metastatic deposits , 4 had myeloid leukomoid reaction ,4 had lymphoma inltration and 2 had hairy cell leukemia . Sex- and age-related distribution of the various disorders was also presented. CONCLUSION: The anemias of all types were the most frequently encountered diagnosis followed by acute and chronic leukemias , ITP , Hypersplenism , ,myeloproliferative disorder , visceral leishmaniasis , malaria, myelodysplastic syndrome and congenital syndromes respectively. The other haematological disorders were less common. These ndings are comparable with published data in previous studies done in Yemen and other developing countries

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