Myeloproliferative Disorders and its Effect on Bone Homeostasis: The Role of Megakaryocytes

Blood ◽  
2021 ◽  
Author(s):  
Katya Ravid ◽  
Aikaterini Karagianni
Keyword(s):  
Bone Health ◽  
Current Knowledge ◽  
Bone Development ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Osteoporotic Fractures ◽  
Clonal Expansion ◽  
Bone Homeostasis ◽  
Hematopoietic Stem

Myeloproliferative Neoplasms (MPNs) are a heterogeneous group of chronic hematological diseases that arise from the clonal expansion of abnormal hematopoietic stem cells, of which Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF) have been extensively reviewed in context of clonal expansion, fibrosis and other phenotypes. Here, we review current knowledge on the influence of different forms of MPN on bone health. Studies implicated various degrees of effect of different forms of MPN on bone density, and on osteoblast proliferation and differentiation, using murine models and human data. The majority of studies show that bone volume is generally increased in PMF patients, whereas it is slightly decreased or not altered in ET and PV patients, although possible differences between male and female phenotypes were not fully explored in most MPN forms. Osteosclerosis seen in PMF patients is a serious complication that can lead to bone marrow failure, and the loss of bone reported in some ET and PV patients can lead to osteoporotic fractures. Some MPN forms are associated with increased number of megakaryocytes (MKs), and several of the MK-associated factors in MPN are known to affect bone development. Here, we review known mechanisms involved in these processes, with focus on the role of MKs and secreted factors. Understanding MPN-associated changes in bone health could improve early intervention and treatment of this side effect of the pathology.

scholarly journals Helicobacter pylori Related Diseases and Osteoporotic Fractures (Narrative Review)

2020 ◽  
Vol 9 (10) ◽  
pp. 3253
Author(s):  
Leon Fisher ◽  
Alexander Fisher ◽  
Paul N Smith
Keyword(s):  
Helicobacter Pylori ◽  
Current Knowledge ◽  
Relevant Literature ◽  
Osteoporotic Fractures ◽  
Holistic Approach ◽  
Chronic Atrophic Gastritis ◽  
Bone Homeostasis ◽  
Digestive Diseases ◽  
Step Algorithm

Osteoporosis (OP) and osteoporotic fractures (OFs) are common multifactorial and heterogenic disorders of increasing incidence. Helicobacter pylori (H.p.) colonizes the stomach approximately in half of the world’s population, causes gastroduodenal diseases and is prevalent in numerous extra-digestive diseases known to be associated with OP/OF. The studies regarding relationship between H.p. infection (HPI) and OP/OFs are inconsistent. The current review summarizes the relevant literature on the potential role of HPI in OP, falls and OFs and highlights the reasons for controversies in the publications. In the first section, after a brief overview of HPI biological features, we analyze the studies evaluating the association of HPI and bone status. The second part includes data on the prevalence of OP/OFs in HPI-induced gastroduodenal diseases (peptic ulcer, chronic/atrophic gastritis and cancer) and the effects of acid-suppressive drugs. In the next section, we discuss the possible contribution of HPI-associated extra-digestive diseases and medications to OP/OF, focusing on conditions affecting both bone homeostasis and predisposing to falls. In the last section, we describe clinical implications of accumulated data on HPI as a co-factor of OP/OF and present a feasible five-step algorithm for OP/OF risk assessment and management in regard to HPI, emphasizing the importance of an integrative (but differentiated) holistic approach. Increased awareness about the consequences of HPI linked to OP/OF can aid early detection and management. Further research on the HPI–OP/OF relationship is needed to close current knowledge gaps and improve clinical management of both OP/OF and HPI-related disorders.

scholarly journals Transplantation for bone marrow failure: current issues

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 90-98 ◽  
Author(s):  
Régis Peffault de Latour
Keyword(s):  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Human Leukocyte ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Sibling Donor ◽  
Alternative Donor

Abstract The preferred treatment of idiopathic aplastic anemia (AA) is allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)–identical sibling donor. Transplantation from a well-matched unrelated donor (MUD) may be considered for patients without a sibling donor after failure of immunosuppressive therapy, as may alternative transplantation (mismatched, cord blood or haplo-identical HSCT) for patients without a MUD. HSCT may also be contemplated for congenital disorders in cases of pancytopenia or severe isolated cytopenia. Currently, HSCT aims are not only to cure patients but also to avoid long-term complications, notably chronic graft-versus-host disease (GVHD), essential for a good quality of life long term. This paper summarizes recent advances in HSCT for idiopathic and inherited AA disorders. The effect of age on current transplantation outcomes, the role of transplantation in paroxysmal nocturnal hemoglobinuria, and the prevention of GVHD are also discussed. Emerging strategies regarding the role of up-front unrelated donor and alternative donor HSCT in idiopathic AA, along with advances in the treatment of clonal evolution in Fanconi anemia, are also examined.

scholarly journals The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2316
Author(s):  
Lucia Catani ◽  
Michele Cavo ◽  
Francesca Palandri
Keyword(s):  
Extracellular Vesicles ◽  
Immune Escape ◽  
Myeloproliferative Neoplasms ◽  
Cell Communication ◽  
Bioactive Molecules ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Patients Experience

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of bioactive molecules such as nucleic acids, proteins, metabolites and lipids. Growing interest is focused on EVs and their potential impact on the regulation of blood cancers. Overall, EVs have been suggested to orchestrate the complex interplay between tumor cells and the microenvironment with a pivotal role in “education” and “crafting” of the microenvironment by regulating angiogenesis, coagulation, immune escape and drug resistance of tumors. This review is focused on the role of EVs in MPN. Specifically, we will provide an overview of recent findings on the involvement of EVs in MPN pathogenesis and discuss opportunities for their potential application as diagnostic and prognostic biomarkers.

scholarly journals T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura Kiekens ◽  
Wouter Van Loocke ◽  
Sylvie Taveirne ◽  
Sigrid Wahlen ◽  
Eva Persyn ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Current Knowledge ◽  
Functional Differentiation ◽  
Cell Maturation ◽  
Hematopoietic Stem ◽  
And Function

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.

scholarly journals Rac signaling in osteoblastic cells is required for normal bone development but is dispensable for hematopoietic development

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 736-744 ◽  
Author(s):  
Steven W. Lane ◽  
Serena De Vita ◽  
Kylie A. Alexander ◽  
Ruchan Karaman ◽  
Michael D. Milsom ◽  
...  
Keyword(s):  
Bone Growth ◽  
Bone Development ◽  
Long Bone ◽  
Perivascular Niche ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Rac1 Gtpase

Abstract Hematopoietic stem cells (HSCs) interact with osteoblastic, stromal, and vascular components of the BM hematopoietic microenvironment (HM) that are required for the maintenance of long-term self-renewal in vivo. Osteoblasts have been reported to be a critical cell type making up the HSC niche in vivo. Rac1 GTPase has been implicated in adhesion, spreading, and differentiation of osteoblast cell lines and is critical for HSC engraftment and retention. Recent data suggest a differential role of GTPases in endosteal/osteoblastic versus perivascular niche function. However, whether Rac signaling pathways are also necessary in the cell-extrinsic control of HSC function within the HM has not been examined. In the present study, genetic and inducible models of Rac deletion were used to demonstrate that Rac depletion causes impaired proliferation and induction of apoptosis in the OP9 cell line and in primary BM stromal cells. Deletion of Rac proteins caused reduced trabecular and cortical long bone growth in vivo. Surprisingly, HSC function and maintenance of hematopoiesis in vivo was preserved despite these substantial cell-extrinsic changes. These data have implications for therapeutic strategies to target Rac signaling in HSC mobilization and in the treatment of leukemia and provide clarification to our evolving concepts of HSC-HM interactions.

scholarly journals Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2250
Author(s):  
Nicolas Chatain ◽  
Steffen Koschmieder ◽  
Edgar Jost
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloproliferative Neoplasms ◽  
Signs And Symptoms ◽  
Clonal Expansion ◽  
Janus Kinase ◽  
Inflammatory Factors ◽  
Disease Pathogenesis ◽  
Hematopoietic Stem

Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT.

scholarly journals Pulmonary Complications After Pediatric Stem Cell Transplant

2021 ◽  
Vol 11 ◽  
Author(s):  
Taylor Fitch ◽  
Kasiani C. Myers ◽  
Maya Dewan ◽  
Christopher Towe ◽  
Christopher Dandoy
Keyword(s):  
Stem Cell ◽  
Current Knowledge ◽  
Bone Marrow Failure ◽  
Current Treatment ◽  
Infectious Complications ◽  
Pulmonary Complications ◽  
Diagnostic Workup ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Bone Marrow Failure Syndromes

The number of disorders that benefit from hematopoietic stem cell transplantation (HSCT) has increased, causing the overall number of HSCT to increase accordingly. Disorders treated by HSCT include malignancy, benign hematologic disorders, bone marrow failure syndromes, and certain genetic diagnoses. Thus, understanding the complications, diagnostic workup of complications, and subsequent treatments has become increasingly important. One such category of complications includes the pulmonary system. While the overall incidence of pulmonary complications has decreased, the morbidity and mortality of these complications remain high. Therefore, having a clear differential diagnosis and diagnostic workup is imperative. Pulmonary complications can be subdivided by time of onset and whether the complication is infectious or non-infectious. While most infectious complications have clear diagnostic criteria and treatment courses, the non-infectious complications are more varied and not always well understood. This review article discusses pulmonary complications of HSCT recipients and outlines current knowledge, gaps in knowledge, and current treatment of each complication. This article includes some adult studies, as there is a significant paucity of pediatric data.

scholarly journals Bleeding diathesis in mice lacking JAK2 in platelets

2021 ◽  
Vol 5 (15) ◽  
pp. 2969-2981
Author(s):  
Nathan Eaton ◽  
Saravanan Subramaniam ◽  
Marie L. Schulte ◽  
Caleb Drew ◽  
David Jakab ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Cytokine Signaling ◽  
Hematopoietic Stem ◽  
Shear Rates ◽  
Granule Secretion ◽  
Static Conditions ◽  
Activation Motif

Abstract The tyrosine kinase JAK2 is a critical component of intracellular JAK/STAT cytokine signaling cascades that is prevalent in hematopoietic cells, such as hematopoietic stem cells and megakaryocytes (MKs). Individuals expressing the somatic JAK2 V617F mutation commonly develop myeloproliferative neoplasms (MPNs) associated with venous and arterial thrombosis, a leading cause of mortality. The role of JAK2 in hemostasis remains unclear. We investigated the role of JAK2 in platelet hemostatic function using Jak2fl/fl Pf4-Cre (Jak2Plt−/−) mice lacking JAK2 in platelets and MKs. Jak2Plt−/− mice developed MK hyperplasia and splenomegaly associated with severe thrombocytosis and bleeding. This notion was supported by failure to occlude in a ferric chloride carotid artery injury model and by a cremaster muscle laser-induced injury assay, in which Jak2Plt−/− platelets failed to form stable thrombi. Jak2Plt−/− platelets formed thrombi poorly after adhesion to type 1 collagen under arterial shear rates. Jak2Plt−/− platelets spread poorly on collagen under static conditions or on fibrinogen in response to the collagen receptor GPVI-specific agonist, collagen-related peptide (CRP). After activation with collagen, CRP, or the CLEC-2 agonist rhodocytin, Jak2Plt−/− platelets displayed decreased α-granule secretion and integrin αIIbβ3 activation or aggregation, but showed normal responses to thrombin. Jak2Plt−/− platelets had impaired intracellular signaling when activated via GPVI, as assessed by tyrosine phosphorylation. Together, the results show that JAK2 deletion impairs platelet immunoreceptor tyrosine-based activation motif signaling and hemostatic function in mice and suggest that aberrant JAK2 signaling in patients with MPNs affects GPVI signaling, leading to hemostatic platelet function.

scholarly journals FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC

2020 ◽  
Author(s):  
Makiko Mochizuki-Kashio ◽  
Young me Yoon ◽  
Theresa Menna ◽  
Markus Grompe ◽  
Peter Kurre
Keyword(s):  
Nuclear Localization ◽  
Fetal Liver ◽  
Bone Marrow Failure ◽  
Physiological Role ◽  
Replication Stress ◽  
S Phase ◽  
Core Component ◽  
Hematopoietic Stem ◽  
Pool Formation

ABSTRACTBone marrow failure (BMF) in Fanconi Anemia (FA) results from exhaustion of hematopoietic stem cells (HSC), but the physiological role of FA proteins in HSC pool integrity remains unknown. Herein we demonstrate that FANCD2, a core component of the FA pathway, counters replication stress during developmental HSC expansion in the fetal liver (FL). Rapid rates of proliferation and FANCD2 deficient result in excess RPA-coated ssDNA, and provoke pChk1 activation and Cdkn1a(p21) nuclear localization in fetal Fancd2−/− HSC. Checkpoint mediated S-phase delays induced by Cdkn1a(p21) are rescued by Tgf-β inhibition, but pChk1 activation is further aggravated. Our observations reveal the mechanism and physiological context by which FANCD2 safeguards HSC pool formation during development.

scholarly journals Loss of the homologous recombination generad51leads to Fanconi anemia-like symptoms in zebrafish

2016 ◽  
Author(s):  
Jan Gregor Botthof ◽  
Ewa Bielczyk-Maczyńska ◽  
Lauren Ferreira ◽  
Ana Cvejic
Keyword(s):  
Bone Marrow ◽  
Homologous Recombination ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Tumor Development ◽  
Embryonic Stem ◽  
Dominant Negative ◽  
Hematopoietic Stem ◽  
Recombination Protein

AbstractRAD51is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant negative mutations. FA is a hereditary DNA repair disorder characterized by various congenital abnormalities, progressive bone marrow failure and cancer predisposition. In this paper, we describe the first viable vertebrate model ofRAD51loss. Zebrafishrad51loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to crosslinking agents and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Co-mutation ofp53was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment ofRAD51as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this novel zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.Significance statementThe homologous recombination protein RAD51 has been extensively studied in prokaryotes and lower eukaryotes. However, there is a significant lack of knowledge of the role of this protein and its regulation in anin-vivocontext in vertebrates. Here we report the first viable vertebrate mutant model ofrad51in zebrafish. These mutant fish enabled us to confirm for the first time the recently discovered role ofRAD51in Fanconi anemia pathogenesis. We report that p53 linked embryonic stem cell defects directly lead to hematological impairments later in life. Co-mutation ofrad51withp53rescues the observed hematological defects, but predisposes the fish to early tumor development. The application of this model opens new possibilities to advance Fanconi anemia drug discovery.

Sign in / Sign up

Export Citation Format

Share Document