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1.
Monosomy 7 arises as a recurrent chromosome aberration in donor cell leukemia after hematopoietic stem cell transplantation. We report a new case of donor cell leukemia with monosomy 7 following HLA-identical allogenic bone marrow transplantation for severe aplastic anemia (SAA). The male patient received a bone marrow graft from his sister, and monosomy 7 was detected only in the XX donor cells, 34 months after transplantation. The patient’s bone marrow microenvironment may have played a role in the leukemic transformation of the donor hematopoietic cells.  相似文献   

2.
3.
Aplastic anemia or bone marrow failure often develops as an effect of chemotherapeutic drug application for the treatment of various pathophysiological conditions including cancer. The long-term bone marrow injury affects the basic hematopoietic population including hematopoietic stem/progenitor cells (HSPCs). The present study aimed in unearthing the underlying mechanisms of chemotherapeutics mediated bone marrow aplasia with special focus on altered redox status and associated effects on hematopoietic microenvironment and epigenetic status of hematopoietic cells. The study involves the development of busulfan and cyclophosphamide mediated mouse model for aplastic anemia, characterization of the disease with blood and marrow analysis, cytochemical examinations of bone marrow, flowcytometric analysis of hematopoietic population and microenvironmental components, determination of ROS generation, apoptosis profiling, expressional studies of Notch-1 signaling cascade molecules, investigation of epigenetic modifications including global CpG methylation of DNA, phosphorylation of histone-3 with their effects on bone marrow kinetics and expressional analysis of the anti-oxidative molecules viz; SOD-2 and Sdf-1. Severe hematopoietic catastrophic condition was observed during aplastic anemia which involved peripheral blood pancytopenia, marrow hypocellularity and decreased hematopoietic stem/progenitor population. Generation of ROS was found to play a central role in the cellular devastation in aplastic marrow which on one hand can be correlated with the destruction of hematopoiesis supportive niche components and alteration of vital Notch-1 signaling and on other hand was found to be associated with the epigenetic chromatin modifications viz; global DNA CpG hypo-methylation, histone-3 phosphorylation promoting cellular apoptosis. Decline of anti-oxidant components viz; Sdf-1 and SOD-2 hinted towards the irreversible nature of the oxidative damage during marrow aplasia. Collectively, the findings hinted towards the mechanistic correlation among ROS generation, microenvironmental impairment and epigenetic alterations that led to hematopoietic catastrophe under aplastic stress. The findings may potentiate successful therapeutic strategy development for the dreadful condition concerned.  相似文献   

4.
The myelodysplastic syndromes (MDS) are clonal hematologic malignancies characterized by pancytopenia, dysplastic hematopoiesis, and a propensity to leukemic transformation. Increased apoptosis has been noted in MDS as a possible explanation for ineffective hematopoiesis, with lower levels in progression to and in de novo acute leukemia. Apoptosis can be measured by binding of Annexin V to exposed membrane phosphatidylserine. We postulated that the apoptotic index would aid in the differential diagnosis of MDS versus other hematopoietic diseases. We examined 33 bone marrow aspirates suspected of hematopoietic malignancy for apoptotic index by Annexin V analysis using a Becton Dickinson FACStar+ flow cytometer. The apoptotic index was expressed as the percentage of Annexin V-positive cells divided by total mononuclear cells in the gate. By standard morphologic analysis, 16 cases were diagnosed as MDS (9 refractory anemia [RA], 2 refractory anemia with ringed sideroblasts [RARS], 1 refractory anemia with excess of blasts [RAEB], 3 chronic myelomonocytic leukemia [CMML], and 1 unclassified), 11 as acute leukemia (AL), 6 as myeloproliferative disorders (MPD). Eight cases (uninvolved marrow of five patients with lymphoproliferative disorders [LPD], one patient with multiple myeloma, and two patients with anemia of chronic disease) served as nonneoplastic controls. A higher degree of apoptosis was observed in MDS (mean = 44.7%; range = 29.5--60%) compared with MPD (mean = 8.2%; range = 2.3--15.4%), AL (mean = 16.1%; range = 5.1--29.4%), and control marrow samples (mean = 11.6%; range = 1.5--21%). Additionally, the apoptotic index was significantly higher in MDS compared with MPD (P < 0.0001). In conclusion, a high apoptotic index occurs in MDS, supporting previous reports and suggesting that Annexin V analysis can be used as an adjunct in the diagnosis of MDS versus MPD. This would be particularly useful for the often-difficult distinction between early MDS and early MPD cases with equivocal morphology.  相似文献   

5.
Peng H  Wen J  Zhang L  Li H  Chang CC  Zu Y  Zhou X 《Molecular bioSystems》2012,8(4):1366-1374
Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases. In addition to intrinsic genetic alterations, the effects of the extrinsic microenvironment also play a pathological role in MDS development. The presence of increased inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), in marrow and abnormal activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in hematopoietic cells are associated with the ineffective hematopoiesis in MDS. However, the molecular mechanism of p38 MAPK activation triggered by microenvironment cytokines remains poorly understood. To address this question, we combined computational modeling analysis and molecular biology studies to perform a systematic investigation of signaling events regulated by microenvironment cytokines in hematopoietic cells from MDS patients. We examined dynamic changes of key signaling events, including the p38 MAPK and the c-Jun N-terminal kinase (JNK) pathway in bone marrow mononuclear cells from MDS patients or normal donors in response to TNF-α stimulation using reverse phase protein array technology. The results were analyzed by a novel computational model and preliminarily validated by immunohistochemistry analysis of the bone marrow tissues from twelve MDS patients and normal donors. Our systematic model revealed that the dynamic response patterns of p38 MAPK and JNK to TNF-α stimulation in MDS were different from that observed in normal marrow cells. Particularly, B-cell lymphoma-X (BCL-XL) protein degradation was regulated by the JNK pathway in normal cells, but by p38 MAPK in MDS cells. By immunohistochemistry, BCL-XL was highly expressed in hematopoietic cells from normal marrow, but was minimally expressed in MDS marrow. Additionally, immunostaining for phosphorylated p38 MAPKα showed much higher p38 MAPK activation in MDS marrows, supporting over-activation of p38 MAPK-enhanced degradation of BCL-XL in MDS. The degradation of BCL-XL triggered by p38 MAPK over-activation may contribute to the increasing apoptosis of marrow cells, a phenomenon commonly observed in MDS, and lead to ineffective hematopoiesis. Our study suggests that the combination of molecular biological studies and systematic modeling is a powerful tool for comprehensive investigation of the complex cellular mechanisms involved in MDS pathogenesis.  相似文献   

6.
Wnts are a family of evolutionary-conserved secreted signaling molecules critically involved in a variety of developmental processes and in cell fate determination. A growing body of evidence suggests that Wnt signaling plays a crucial role in the influence of bone marrow stromal microenvironment on the balance between hematopoietic stem cell self-renewal and differentiation. Emerging clinical and experimental evidence also indicates Wnt signaling involvement in the disruption of the latter balance in hematologic malignancies, where the stromal microenvironment favors the homing of cancer cells to the bone marrow, as well as leukemia stem cell development and chemoresistance. In the present review, we summarize and discuss the role of the canonical Wnt signaling pathway in normal hematopoiesis and hematologic malignancies, with regard to recent findings on the stromal microenvironment involvement in these process and diseases.  相似文献   

7.
D Haase  C Fonatsch 《Blut》1990,60(3):192-197
The influence of GM-CSF on bone marrow cultures from 13 patients with aplastic anemia, MDS and acute leukemia was studied in a short-term suspension culture system. In each case combined cytogenetic and proliferation analyses were performed with respect to the question, whether chromosome aberrations play a role in the in vitro response to GM-CSF and in order to search for stimulating effects on malignant cells. The responsiveness was compared of aplastic and myelodysplastic cultures on the one hand and of leukemic cells on the other. Our results show that myelodysplastic and aplastic cells display a tendency for reduced susceptibility to GM-CSF as compared to healthy controls, while in leukemic bone marrow the response to the growth factor was significantly enhanced, indicating a leukemia-specific response pattern. In the majority of leukemias analyzed, the presence of cytogenetically abnormal cells in cultures with excessive response to GM-CSF can be taken as a proof for stimulation of malignant cells. The significance of these findings for pathogenesis and prognosis in aplastic anemia, myelodysplasia and leukemia is discussed.  相似文献   

8.
Post-mortem examination of two cases of natural Haemobartonella felis infection in the cat is reported. In both cases haemobartonellosis was confirmed on blood smears from the diseased animals. The most noticeable macroscopic finding was a pronounced general anemia. The microscopic examination revealed hyperplasia of the bone marrow and a moderate extramedullary hematopoiesis in case 1 and in case 2 a reduction of the M/E index in the bone marrow.  相似文献   

9.
Q X Li  H Fan 《Journal of virology》1991,65(8):4442-4448
We previously described a preleukemic state induced by Moloney murine leukemia virus (Mo-MuLV) characterized by hematopoietic hyperplasia in the spleen. Further experiments suggested that splenic hyperplasia results from inhibitory effects in the bone marrow, leading to compensatory extramedullary hematopoiesis. An enhancer variant of Mo-MuLV, Mo + PyF101 Mo-MuLV, fails to induce preleukemic hyperplasia and has greatly reduced leukemogenicity, indicating the importance of this state to efficient leukemogenesis. An alternative method for induction of preleukemic hyperplasia was sought. Treatment of mice with 89Sr causes specific ablation of bone marrow hematopoiesis and compensatory extramedullary hematopoiesis in spleen and nodes. NIH Swiss mice were inoculated neonatally with Mo + PyF101 Mo-MuLV and treated with 89Sr at 6 weeks of age. Approximately 85% developed lymphoid leukemia with a time course resembling that caused by wild-type Mo-MuLV. In contrast, very few animals treated with Mo + PyF101 Mo-MuLV or 89Sr alone developed disease. In approximately one-third of cases, the Mo + PyF101 Mo-MuLV proviruses were found at common sites for wild-type Mo-MuLV-induced tumors (c-myc, pvt-1, and pim-1), indicating that this virus is capable of performing insertional activation in T-lymphoid cells. These results support the proposal that splenic hyperplasia results from inhibitory effects in the bone marrow. They also indicate that Mo + PyF101 Mo-MuLV is blocked in early and not late events in leukemogenesis.  相似文献   

10.
During embryonic life, hematopoiesis occurs first in the yolk sac, followed by the aorto-gonado-mesonephric region, the fetal liver, and the bone marrow. The possibility of hematopoiesis in other embryonic sites has been suspected for a long time. With the use of different methodologies (transgenic mice, electron microscopy, laser capture microdissection, organ culture, and cross-transplant experiments), we show that multiple regions within the embryo are capable of forming blood before and during organogenesis. This widespread phenomenon occurs by hemo-vasculogenesis, the formation of blood vessels accompanied by the simultaneous generation of red blood cells. Erythroblasts develop within aggregates of endothelial cell precursors. When the lumen forms, the erythroblasts "bud" from endothelial cells into the forming vessel. The extensive hematopoietic capacity found in the embryo helps explain why, under pathological circumstances such as severe anemia, extramedullary hematopoiesis can occur in any adult tissue. Understanding the intrinsic ability of tissues to manufacture their own blood cells and vessels has the potential to advance the fields of organogenesis, regeneration, and tissue engineering.  相似文献   

11.
The bone marrow (BM) is an essential organ for hematopoiesis in adult, in which proliferation and differentiation of hematopoietic stem/progenitor cells (HSPC) is orchestrated by various stromal cells. Alterations of BM hematopoietic environment lead to various hematopoietic disorders as exemplified by the linking of fatty marrow with increased adipogenesis to anemia or pancytopenia. Therefore, the composition of mesenchymal stromal cell (MSC)-derived cells in the BM could be crucial for proper hematopoiesis, but the mechanisms underlying the MSC differentiation for hematopoiesis remain poorly understood. In this study, we show that Oncostatin M (OSM) knock out mice exhibited pancytopenia advancing fatty marrow with age. OSM strongly inhibited adipogenesis from BM MSC in vitro, whereas it enhanced their osteogenesis but suppressed the terminal differentiation. Intriguingly, OSM allowed the MSC-derived cells to support the ex vivo expansion of HSPC effectively as feeder cells. Furthermore, the administration of OSM in lethally irradiated wild-type mice blocked fatty marrow and enhanced the recovery of HSPC number in the BM and peripheral blood cells after engraftment of HSPC. Collectively, OSM plays multiple critical roles in the maintenance and development of the hematopoietic microenvironment in the BM at a steady state as well as after injury.  相似文献   

12.
SDF-1 and CXCR4 in normal and malignant hematopoiesis   总被引:12,自引:0,他引:12  
Over recent years it has become apparent that the chemokine SDF-1 and its receptor CXCR4 play pivotal roles in normal hematopoiesis. They are essential for the normal ontogeny of hematopoiesis during embryogenesis and continue to play a key role in retaining hematopoietic progenitors within the bone marrow microenvironment in the adult. As a result of this role disruption of SDF-1/CXCR4 interactions results in mobilization of hematopoietic progenitors and standard mobilization protocols disrupt this axis. Similarly SDF-1/CXCR4 interactions are required for homing and engraftment of hematopoietic stem cells during transplantation. SDF-1 regulates the localisation of leukemic cells and like their normal counterparts most leukemic cells respond to SDF-1 with increased adhesion, survival and proliferation. However in some instances leukemic cell responses to SDF-1 can be disregulated, the impact of which on the progression of disease in not known. In this review we discuss the pleiotropic roles of SDF-1/CXCR4 interactions in human hematopoietic stem cell ontogeny, bone marrow homing and engraftment, mobilization and how these interactions impact on malignant hematopoiesis.  相似文献   

13.
Myelodysplastic syndromes (MDS) are triggered by an aberrant hematopoietic stem cell (HSC). It is, however, unclear how this clone interferes with physiologic blood formation. In this study, we followed the hypothesis that the MDS clone impinges on feedback signals for self-renewal and differentiation and thereby suppresses normal hematopoiesis. Based on the theory that the MDS clone affects feedback signals for self-renewal and differentiation and hence suppresses normal hematopoiesis, we have developed a mathematical model to simulate different modifications in MDS-initiating cells and systemic feedback signals during disease development. These simulations revealed that the disease initiating cells must have higher self-renewal rates than normal HSCs to outcompete normal hematopoiesis. We assumed that self-renewal is the default pathway of stem and progenitor cells which is down-regulated by an increasing number of primitive cells in the bone marrow niche – including the premature MDS cells. Furthermore, the proliferative signal is up-regulated by cytopenia. Overall, our model is compatible with clinically observed MDS development, even though a single mutation scenario is unlikely for real disease progression which is usually associated with complex clonal hierarchy. For experimental validation of systemic feedback signals, we analyzed the impact of MDS patient derived serum on hematopoietic progenitor cells in vitro: in fact, MDS serum slightly increased proliferation, whereas maintenance of primitive phenotype was reduced. However, MDS serum did not significantly affect colony forming unit (CFU) frequencies indicating that regulation of self-renewal may involve local signals from the niche. Taken together, we suggest that initial mutations in MDS particularly favor aberrant high self-renewal rates. Accumulation of primitive MDS cells in the bone marrow then interferes with feedback signals for normal hematopoiesis – which then results in cytopenia.  相似文献   

14.
Gough SM  Chung YJ  Aplan PD 《PloS one》2012,7(5):e36876
Myelodysplastic syndrome (MDS) and aplastic anemia (AA) patients both present with symptoms of bone marrow failure. In many AA patients, these features are thought to result from an oligoclonal expansion of cytotoxic T-cells that destroy haematopoietic stem or progenitor cells. This notion is supported by the observation that AA patients respond to immunosuppressive therapy. A fraction of MDS patients also respond well to immunosuppressive therapy suggesting a similar role for cytotoxic T-cells in the etiology of MDS, however the role of cytotoxic T-cells in MDS remains unclear. Mice that express a NUP98-HOXD13 (NHD13) transgene develop a MDS that closely mimics the human condition in terms of dysplasia, ineffective hematopoiesis, and transformation to acute myeloid leukemia (AML). We followed a cohort of NHD13 mice lacking the Rag1 protein (NHD13/Rag1KO) to determine if the absence of lymphocytes might 1) delay the onset and/or diminish the severity of the MDS, or 2) effect malignant transformation and survival of the NHD13 mice. No difference was seen in the onset or severity of MDS between the NHD13 and NHD13/Rag1KO mice. However, NHD13/Rag1KO mice had decreased survival and showed a trend toward increased incidence of transformation to AML compared to the NHD13 mice, suggesting protection from AML transformation by a modest immuno-surveillance effect. In the absence of functional Tcrb signaling in the NHD13/Rag1KO T-cell tumors, Pak7 was identified as a potential Tcrb surrogate survival signal.  相似文献   

15.
Our previous study indicated that injecting nitrogen-containing bisphosphonate (NBP) induced the site of erythropoiesis to shift from the bone marrow (BM) to the spleen. This was due to the depletion of BM-resident macrophages, which support erythropoiesis. In this study, we examined NBP treatment-induced extramedullary hematopoiesis in splenectomized mice, focusing on hepatic hematopoiesis. NBP-treated mice did not display anemia or significant change in erythropoietin production, while megakaryopoiesis and erythropoiesis were constantly observed in the liver. Erythroblastic islands were detected in the sinusoidal lumen. Kupffer cells expressed VCAM-1 following NBP treatment, which is an important factor for erythroblast differentiation. Cl2MBP-liposome treatment depleted the erythroblastic islands, and decreased the number of hematopoietic cells in the liver, as determined by colony forming assays. Together, these results indicate that Kupffer cells support erythropoiesis, acting as stromal cells in the liver, and that they might act as a niche for hematopoietic precursor cells in an emergency.  相似文献   

16.
BACKGROUND: Extramedullary hematopoiesis is a compensatory phenomenon that occurs when normal function of the bone marrow is disturbed. It is most often seen in patients with hematologic disorders. Although the sites most frequently involved are the spleen, liver and lymph nodes, other organs may be involved. We report on 2 cases of extra-medullary hematopoiesis mimicking posterior mediastinum and paravesical tumors and diagnosed by fine needle aspiration cytology. CASES: Two men, aged 72 and 82 years, with hemolytic anemia (thalassemia intermedia and idiopathic) presented with solid masses involving the posterior mediastinum and paravesical region. The patients underwent computed tomography-guided fine needle aspiration. The smears were composed of normal bone marrow elements. Both cases were diagnosed as extramedullary hematopoiesis. CONCLUSION: Fine needle aspiration cytology is an useful method of diagnosing extramedullary hematopoiesis and aids in planning treatment.  相似文献   

17.
18.
Bone marrow hypoplasia was characterized in a group of female ferrets during prolonged estrus. All ferrets exhibited hematological changes characteristic of various degrees of bone marrow hypoplasia. Hematological findings included initial thrombocytosis and leukocytosis followed by thrombocytopenia, leukopenia and anemia. Platelet counts below 50,000/microliters were observed in 55% of the ferrets. Hemorrhagic anemia due to thrombocytopenia was the most common cause of death and the mortality rate was 40%. Histopathological findings included bone marrow hypoplasia affecting all cell lines and decreased splenic extramedullary hematopoiesis.  相似文献   

19.
Irradiation from γ-rays can cause severe damage to bone marrow and hematopoietic tissues. Presently, the most effective method available to treat severe hematopoietic injury is a bone marrow transplant (BMT). Allogeneic BMT is a difficult technique to perform due to the differences in human leukocyte antigen proteins between the donor and recipient, with acute graft-versus-host disease being a major complication of the technique. This limits the widespread applicability of allogeneic BMT. To develop a novel treatment for acute hematopoietic damage, we transplanted bone marrow derived mesenchymal stem cells (MSCs) into recipient mice and treated them with recombinant human bone morphogenetic protein 2 (rhBMP2) to investigate whether MSCs and rhBMP2 could additively promote the restoration of hematopoietic function. MSCs are vital components of the hematopoietic microenvironment that supports hematopoiesis, and bone morphogenic protein is a key factor in hematopoiesis. The 30-day survival rate as well as the numbers of nucleated cells, bone marrow colony-forming unit-granulocyte macrophages, spleen colony-forming units and peripheral blood cells were enumerated. The results showed that, after γ-irradiation and transplantation, MSCs and rhBMP2 additively promoted and improved hematopoietic restoration and function in vivo and in vitro. This additive effect of MSCs and rhBMP2 may one day provide a novel means of treating acute hematopoietic damage.  相似文献   

20.
MPSV induces a myeloproliferative syndrome in susceptible mice associated with an invasion of hematopoietic and nonhematopoietic organs with tumor nodules. The effect of the virus on the various hematopoietic precursors (CFU-S, CFU-C, CFU-E, BFU-E) was studied in vivo in the spleen, blood, and bone marrow, and in vitro, using colony assays in semisolid medium. After in vivo and in vitro infection MPSV induces the appearance of CFU-C, independent of added colony-stimulating activity and of pure and mixed BFU-E, independent of burst-promoting activity. MPSV also induces in vivo an amplification of the size and concentration of the hematopoietic system, including hematopoietic stem cells. MPSV infection may also alter the hemapoietic microenvironment. Modification of the disease by total body irradiation followed by bone marrow stem cell reconstitution or by splenectomy is compatible with mediation of the virus effect at the level of hematopoietic microenvironment. MPSV may constitute a new tool to study the regulation of murine hematopoiesis and viral genetic information, which can specifically induce characteristic disturbances of this system.  相似文献   

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