Stress Response Gene Egr-1 As Tumor Suppressor in BCR-ABL Mediated Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 33-33
Author(s):  
Silvia Maifrede ◽  
Dan Liebermann ◽  
Barbara Hoffman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Tyrosine Kinase ◽  
Wild Type ◽  
Response Gene ◽  
Cell Compartment ◽  
Stem Cell Compartment ◽  
Novel Targets

Abstract Abstract 33 Chronic Myelogenous Leukemia (CML) is a disease resulting from the neoplastic transformation of hematopoietic stem cells (HSC) with the BCR-ABL oncogene. The BCR-ABL protein is a constitutively active tyrosine kinase, which promotes cell survival and proliferation by means of diverse intracellular signaling pathways, thereby being the culprit for malignant transformation. In the late 1990s a Tyrosine Kinase Inhibitor (TKI), imatinib mesylate (Gleevec, Novartis) started to be effectively used on CML patients. However, imatinib, therapy suppresses rather than eliminates the disease, and resistance to imatinib has been described. Thus there is a high priority to enhance our understanding of how BCR/ABL subverts normal hematopoiesis and to identify novel targets for therapy. The transcription factor early growth response 1 (Egr-1) was identified as a macrophage differentiation primary response gene, shown to be essential for and to restrict differentiation along the macrophage lineage. There's evidence consistent with Egr-1 behaving as a tumor suppressor of leukemia, both in vivo and in vitro, including (1) loss of Egr-1 associated with treatment derived AMLs; (2) deregulated Egr-1 overriding blocks in myeloid differentiation, and (3) haplo-insufficiency of Egr-1 in mice leading to increased development of myeloid disorders following treatment with the potent DNA alkylating agent, N- ethyl-nitrosourea (ENU). Therefore, we chose to investigate if Egr-1 can act as a suppressor of BCR-ABL driven leukemia. To assess the effect of Egr-1 on BCR-ABL driven leukemia, lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr-1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). It was observed that loss of Egr-1 accelerated the development of BCR-ABL driven leukemia in recipient mice. Furthermore, we investigated the stem cell compartment of both Egr-1 WT and Egr-1−/− BM, by determining the percentage of stem cells (Lin−Sca+c-Kit+, LSK), before infection with BCR-ABL; no statistically significant difference in the percentage of LSK cells was observed between Egr-1 WT and Egr-1−/− BM. Thus, the BM stem cell compartment of the Egr-1−/− mice does not offer a quantitiative advantage to justify the faster development of leukemia compared to Egr-1 WT mice. Furthermore, when BM of transplanted mice was analyzed we observed an increased population of lineage negative cells in Egr-1−/− BCR-ABL recipients when compared to animals transplanted with WT BCR-ABL BM, consistent with more rapid development of disease. Preliminary results from serial BMT has shown that Egr-1−/− BCR-ABL BM has an increased leukemic burden when compared to the WT counterpart. Additional data from our animal model, as well as analysis of human leukemia samples will be presented, further corroborating that Egr-1 functions as a suppressor of BCR-ABL driven CML. These data could result in novel targets for diagnosis, prognosis, and targeted therapeutics for CML, as well as for other leukemic diseases. Disclosures: No relevant conflicts of interest to declare.

Stress Response Transcription Factor Egr-1 As Tumor Suppressor Of CML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4905-4905
Author(s):  
Silvia Maifrede ◽  
Dan Liebermann ◽  
Barbara Hoffman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Transcription Factor ◽  
Tumor Suppressor ◽  
Tyrosine Kinase ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Significant Difference ◽  
Novel Targets

The transcription factor early growth response 1 (Egr-1) gene was identified as a macrophage differentiation primary response gene, shown to be essential for and to restrict differentiation along the macrophage lineage. There’s evidence consistent with Egr-1 behaving as a tumor suppressor of leukemia, both in vivo and in vitro, including (1) loss of Egr-1 associated with treatment derived AMLs; (2) deregulated Egr-1 overriding blocks in myeloid differentiation, and (3) haplo-insufficiency of Egr-1 in mice leading to increased development of myeloid disorders following treatment with the potent DNA alkylating agent, N- ethyl-nitrosourea (ENU). BCR-ABL driven leukemia (Chronic Myelogenous Leukemia [CML]) was chosen as a model system to investigate the role of Egr-1 as a tumor suppressor for different leukemias. CML is a disease resulting from the neoplastic transformation of hematopoietic stem cells (HSC) with the BCR-ABL oncogene. The BCR-ABL protein is a constitutively active tyrosine kinase, which promotes cell survival and proliferation by means of diverse intracellular signaling pathways, thereby being the culprit for malignant transformation. Although the Tyrosine Kinase Inhibitor (TKI) imatinib mesylate (Gleevec, Novartis) is effectively used on CML patients, resistance to imatinib has been described. Thus there is a high priority to enhance our understanding of how BCR/ABL subverts normal hematopoiesis and to identify novel targets for therapy. It was observed that Egr-1 expression is reduced in bone marrow (BM) of CML patients, and its expression is further reduced in more advanced stages of CML. Consistent with this data, Egr-1 expression is reduced in BCR-ABL-expressing murine BM. The tumor suppressor role of Egr-1 in CML was validated using mouse models. Lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr-1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). Loss of Egr-1 accelerated the development of BCR-ABL driven leukemia in recipient mice. Furthermore, no statistically significant difference in the percentage of stem cells (Lin-Sca+c-Kit+, LSK) was observed between Egr-1 WT and Egr-1-/- BM. Thus, the BM stem cell compartment of the Egr-1-/- mice does not offer a quantitative advantage to justify the faster development of leukemia compared to Egr-1 WT mice. An increased population of lineage negative BM cells was observed in Egr-1-/- BCR-ABL recipients when compared to animals transplanted with WT BCR-ABL BM, consistent with more rapid development of disease. Preliminary results from serial BMT has shown that Egr-1-/- BCR-ABL BM has an increased leukemic burden when compared to the WT counterpart. Data from serial colony transfer and studies using spleens from diseased mice as well as BCR-ABL-expressing BM will be presented. These data could result in novel targets for diagnosis, prognosis, and targeted therapeutics, including strategies for activating Egr-1 expression, that can be used to treat CML, as well as other leukemic diseases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Stem cells in liver repair

2006 ◽  
Vol 28 (1) ◽  
pp. 11-14
Author(s):  
Yiannis N. Kallis ◽  
Stuart J. Forbes
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Liver Regeneration ◽  
Liver Tissue ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Biliary Tree ◽  
Cell Compartment ◽  
Stem Cell Compartment

The liver can be subjected to many damaging insults, usually from toxins, viral infections, immune or metabolic diseases, during its lifetime. Normal restoration of liver tissue occurs via division of mature functional hepatocytes. In addition, a liver-stem-cell compartment, lying deep within the intrahepatic biliary tree, can be activated during severe or iterative stress. Recent studies have suggested that the bone marrow (BM) may also contribute to liver regeneration, although these observations remain controversial.

The Tumor Suppressor Role of the Msr1 Gene in Cancer Stem Cells of Chronic Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 188-188
Author(s):  
Yaoyu Chen ◽  
Con Sullivan ◽  
Shaoguang Li
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Leukemia Cells ◽  
Wild Type ◽  
Marrow Cells

Abstract Abstract 188 We have previously shown that the arachidonate 5-lipoxygenase gene (Alox5) functions as a critical regulator of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML) in mice (Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). We believe that the Alox5 pathway represents a major molecular network in LSCs. Therefore, we decided to further dissect this pathway by comparing gene expression profiles between wild type and Alox5−/− LSCs from CML mice using the DNA microarray analysis. We identified a small group of candidate genes that were changed in expression in the absence of Alox5. Among these genes, we have identified the Msr1 gene and chosen to test the function of this gene in regulating LSC function, because this gene was up-regulated, indicating that it might play a tumor suppressor role in LSCs. In our CML mouse model, we observed that recipients of BCR-ABL transduced Msr1−/− bone marrow cells developed CML much rapidly than recipients of BCR-ABL transduced wide type bone marrow cells. To test whether this accelerated CML is related to abnormal function of LSCs, we carried out a serial transplantation assay by transferring bone marrow cells from primary recipients of BCR-ABL-transduced wild type or Msr1−/− donor bone marrow cells into secondary and next-generation of recipient mice to biologically assess the effect of Msr1 on LSCs. BCR-ABL-expressing wild type leukemia cells from bone marrow of CML mice were only able to transfer CML once, whereas BCR-ABL-expressing Msr1−/− leukemia cells were able to transfer lethal CML for five genrations. This observation indicates that BCR-ABL-expressing Msr1−/− LSCs have markedly increased stem cell function. To further compare the stem cell function, we performed the leukemia stem cell competition assay by 1:1 mixing wild type (CD45.1) and Msr1−/− (CD45.2) bone marrow cells from CML mice. At day 25 or 30 after transplantation, more than 60% and 95% of GFP+Gr-1+ cells in peripheral blood of the mice were CD45.2+Msr1−/− myeloid leukemia cells, and all these mice developed CML and died of CML derived from Msr1−/− LSCs. To confirm the tumor suppressor role of Msr1 in CML development, we co-expressed BCR-ABL and Msr1 in MSR1−/− bone marrow cells by retroviral transduction, followed by transplantation of these cells into recipient mice. The ectopically-expressed Msr1 in MSR1−/− bone marrow cells rescued the accelerated CML phenotype, and some recipient mice did not even develop the CML. Together, these results demonstrate that Msr1 plays a tumor suppressor role in LSCs. The Msr1 pathway is a novel molecular network in LSCs, and it will be important to fully study this pathway for developing curative therapeutic strategies for CML. Disclosures: No relevant conflicts of interest to declare.

The Novel AML Stem Cell Associated Antigen CLL-1 Discriminates between Normal and Leukemic Stem Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4-4 ◽  
Author(s):  
Anna van Rhenen ◽  
Nicole Feller ◽  
Angèle Kelder ◽  
Guus Westra ◽  
Lex Bakker ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Clinical Outcome ◽  
Stem Cell Marker ◽  
Cell Detection ◽  
The Novel ◽  
Antibody Treatment ◽  
Cell Compartment ◽  
Stem Cell Compartment

Abstract In CD34-positive acute myeloid leukemia (AML), the leukemia-initiating event likely takes place in the CD34+CD38- stem cell compartment. Survival of these cells after chemotherapy hypothetically leads to minimal residual disease (MRD) and relapse. We have previously shown that a high CD34+CD38- frequency correlates with both MRD frequency, especially after the third course of chemotherapy and poor survival (Clin Cancer Res, in press). Furthermore, we have shown that a monoclonal antibody against the novel cell surface marker C-type lectin-like molecule-1 (CLL-1), directed against myeloid cells, stains 92% of diagnosis AML (Bakker et al., Cancer Res.64:8443, 2004). In the present study we investigated whether this antibody can be used to identify AML stem cells in remission bone marrow. Such would offer opportunities for MRD stem cell detection and stem cell-directed therapy. We found that anti-CLL-1 antibody homogeneously stained the CD34+CD38- compartment in 77/89 cases (median expression of 33.3% in all 89 cases, range 0–100%). The median stem cell expression of CLL-1 in control bone marrow was 0% ranging from 0–11% (n=11). Furthermore, CLL-1 expression on AML stem cells is highly stable: no differences between paired diagnosis and relapse samples (p=0.9, n=12). Like most antigens CLL-1 is expressed on part of the CD34+CD38+ compartment, but expression is absent on megakaryocytic precursors, which for therapeutic use would circumvent delayed platelet recovery. For antibody-mediated therapy it is crucial that normal stem cells remain negative throughout treatment of the disease. Therefore we tested bone marrow regenerating after high dose chemotherapy, obtained from either non-AML hematological patients or CD34 negative or CLL-1 negative AML patients. In those patients complete absence of CLL-1 expression was found in CD34+CD38− cells (n=4). Under MRD-conditions CLL-1 staining thus enables to accurately discriminate between normal and malignant CD34+CD38− stem cells. In agreement with this, the different ratios of AML and normal stem cells that were found in a number of patients, paralleled clinical outcome in terms of probability of relapse. For comparison, the stem cell marker CD123 was studied. Although anti-CD123 antibody homogeneously stained CD34+CD38− cells with high intensity in almost all AML samples studied (35/36 cases) with also no differences between diagnosis and relapse (p=0.6, n=6) and with low expression in normal bone marrow (median 14.9%, range 0–18.8%, n=5), a high expression was found in regenerating bone marrow (median 60%, range 53–84%, n=4). The latter suggests that anti-CD123 antibody is not AML stem cell specific under all conditions of disease. In conclusion, our data provide strong evidence that a large CD34+CD38− population at diagnosis reflects a higher percentage of chemotherapy-resistant cells, which, in remission, will lead to the outgrowth of MRD, thereby affecting clinical outcome. The specificity of anti-CLL-1 antibody under all conditions of disease enables both reliable detection and quantification of the stem cell compartment for prognostic use under MRD conditions, as well as characterization. Moreover, it shows that AML stem cell targeting using antibody treatment at different stages of disease has now become an option in the treatment of AML patients.

Leukemic Stem Cell Assessment in Remission Bone Marrow of Acute Myeloid Leukemia Patients Is a New Prognostic Parameter.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 399-399 ◽  
Author(s):  
Monique Terwijn ◽  
Angèle Kelder ◽  
Arjo P Rutten ◽  
Alexander N Snel ◽  
Willemijn Scholten ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Prognostic Information ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Stem Cell Compartment ◽  
Acute Myeloid

Abstract Abstract 399 In acute myeloid leukemia (AML), relapses originate from the outgrowth of therapy surviving leukemic blasts know as minimal residual disease (MRD). Accumulating evidence shows that leukemia initiating cells or leukemic stem cells (LSCs) are responsible for persistence and outgrowth of AML. Monitoring LSCs during and after therapy might thus offer accurate prognostic information. However, as LSCs and hematopoietic stem cells (HSCs) both reside within the immunophenotypically defined CD34+CD38- compartment, accurate discrimination between LSCs and HSCs is required. We previously showed that within the CD34+CD38- stem cell compartment, LSCs can be discriminated from HSC by aberrant expression of markers (leukemia associated phenotype, LAP), including lineage markers like CD7, CD19 and CD56 and the novel LSC marker CLL-1 (van Rhenen, Leukemia 2007, Blood 2007). In addition, we reported that flowcytometer light scatter properties add to even better detection of LSCs, allowing LSCs detection in AML cases lacking LAP (ASH abstract 1353, 2008). Using this gating strategy, we determined LSC frequency in 64 remission bone marrow samples of CD34+ AML patients. A stem cell compartment was defined as a minimum of 5 clustered CD34+CD38- events with a minimal analyzed number of 500,000 white blood cells. After first cycle of chemotherapy, high LSC frequency (>1 × 10-3) clearly predicted adverse relapse free survival (RFS, figure 1a). LSC frequency above cut-off led to a median RFS of 5 months (n=9), while patients with LSC frequency below cut-off (n=22) showed a significantly longer median RFS of >56 months (p=0.00003). In spite of the relatively low number of patients, again a high LSC frequency (>2 × 10-4) after the second cycle and after consolidation therapy predicted worse RFS: after second cycle, median RFS was 6 months (n=9) vs. >43 months for patients with LSC frequency below cut-off (p=0.004). After consolidation, these figures were 6 months (n=7) vs. >32 months (n=6, p=0.03). Although total blast MRD (leukemic blasts as % of WBC) is known to predict survival (N.Feller et al. Leukemia 2004), monitoring LSCs as compared to total blast MRD has two major advantages: the specificity is higher (van Rhenen et al. Leukemia 2007) and well-known LSC makers like CLL-1, CD96 and CD123 can in principle be used for LSC monitoring, but not for total blast MRD detection since these markers are also expressed on normal progenitor cells. On the other hand, LSCs constitute only a small fraction of all leukemic blasts and therefore monitoring total blast MRD may have the advantage of a higher sensitivity. We thus tested the hypothesis that even more accurate prognostic information could be obtained by combining LSC frequency with total blast MRD. Total blast MRD after first cycle was predictive for survival with borderline significance (p=0.08): a cut-off of 0.3% resulted in two patient groups with median RFS of 9 months vs. >56 months. Figure 1b shows the result of the combined data of LSC and MRD frequency after first cycle therapy. We used the terms LSC+ and MRD+ for cell frequencies above cut-off and LSC- and MRD- for those below cut-off. We could clearly identify that apart from LSC+/MRD+ patients, LSC+/MRD- patients too have very poor prognosis, while MRD+/LSC- patients show an adverse prognosis as compared to LSC-/MRD- patients. These results from the first study on the in vivo fate of LSCs during and after therapy, strongly support the hypothesis that in CD34+ AML the leukemia initiating capacity originates from the CD34+CD38- population and is important for tumor survival and outgrowth. These results show that LSC frequency might be superior in predicting prognosis of AML patients in CR as compared to MRD total blast frequency, while the combination of both may offer the most optimal parameter to guide future intervention therapies. This work was supported by Netherlands Cancer Foundation KWF. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hematopoietic stem cells: effect of preirradiation, bleeding, and erythropoietin on thrombopoietic differentiation

Blood ◽  
1977 ◽  
Vol 49 (2) ◽  
pp. 253-261 ◽  
Author(s):  
R Goodman ◽  
H Grate ◽  
E Hannon ◽  
S Hellman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Proliferative Activity ◽  
Bone Marrow Cells ◽  
Cell Compartment ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem Cell Compartment ◽  
Cell Assays

Abstract A method of measuring differentiation of stem cells towards platelets is described using syngeneic bone marrow injected into lethally irradiated mice. Fourteen days after such injection, the platelet counts are found to be proportional to the number of bone marrow cells injected and can be used as a measure of platelet progenitors. Perturbation of the milieu in which the transplanted marrow is placed by host preirradiation, bleeding, or erythropoietin administration leads to enhanced thrombopoiesis. It has been shown previously that similar perturbation favors erythropoiesis at the expense of granulopoiesis. The data from these and other experiments appear to be consistent, with a model of the stem cell compartment as a continuum with proliferative activity increasing as commitment is restricted. These functions vary inversely with the capacity for self-renewal. The various stem cell assays measure different ranges of stem cells, but overlap within this continuum.

scholarly journals Effect of graft-versus-host disease on hematopoiesis after bone marrow transplantation in mice

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2773-2779 ◽  
Author(s):  
PJ van Dijken ◽  
J Wimperis ◽  
JM Crawford ◽  
JL Ferrara
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cell Compartment ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host ◽  
Stem Cell Compartment

Abstract We have examined the effect of graft-versus-host disease (GVHD) on the reconstitution of donor hematopoiesis in a murine bone marrow transplant (BMT) model of GVHD to minor histocompatibility antigens. GVHD had no effect on peripheral blood counts, which normalized by 1 month after BMT, and did not affect numbers of hematopoietic progenitors in the BM, which remained decreased in all transplant recipients. Donor stem cells (colony-forming unit-spleen day 8) and stem cell self-renewal remained low in all mice for 5 months after transplant, but GVHD further damaged the stem cell compartment. Peripheral counts 1 month after transplant were supported by increased numbers of stem cells in cycle and increased splenic hematopoiesis. However, GVHD altered the pattern of extramedullary hematopoiesis, causing dramatically decreased activity in the spleen and increased activity in the liver. We conclude that GVHD further decreases hematopoietic reserve and causes damage to the donor stem cell compartment during hematopoietic reconstitution after transplant, despite unaffected progenitor frequencies and peripheral blood counts.

scholarly journals Studies of hematopoietic stem cells spared by 5-fluorouracil.

1984 ◽  
Vol 159 (3) ◽  
pp. 679-690 ◽  
Author(s):  
G Van Zant
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Stem Cell Compartment ◽  
Developmental Maturation ◽  
Marrow Cells

Mouse marrow cells were exposed to 5-fluorouracil (FU) either in vivo or in vitro and the effects on the hematopoietic stem cell compartment were studied. The drug was highly toxic to bone marrow cells including the spleen colony-forming unit (CFU-S) population. The small population of stem cells surviving FU, however, caused a different pattern of spleen colony growth when injected into lethally irradiated mice. Whereas numbers of spleen colonies caused by normal marrow cells remained constant during an 8-14 d period after transplantation, spleen colonies derived from FU-treated marrow cells increased by as much as 100-fold during this time. This effect on stem cells was dose dependent both in vitro and in vivo. When FU was given in vivo, the day 14/day 8 ratio of colonies was greatest 1 d after injection and, over the next 7 d, returned to a near-normal value, that is, unity. A number of studies have shown that the stem cell compartment is heterogeneous with respect to self-replicative capacity and developmental potential. An age structure for the stem cell compartment has been proposed wherein cells with a short mitotic history are more likely to self-replicate than they are to differentiate; hence they are more primitive. 'Older' stem cells with a longer mitotic history are, according to the hypothesis, more likely to differentiate. 5-fluorouracil may be toxic to the older stem cells and selectively spare the more primitive subpopulation. Although the surviving cells may not themselves be able to form spleen colonies, they may give rise to an older cohort of cells more likely to differentiate and form spleen colonies. It is the requisite developmental maturation within the stem cell compartment that may be responsible for the delay in appearance of spleen colonies derived from FU-treated marrow. Our results support this explanation and identify the locus of at least part of this activity as the bone marrow. We found that the FU-treated marrow did not cause an increase in spleen colony numbers between 8 and 14 d in hosts with a long-standing marrow aplasia, due to the incorporation of 89Sr into bone. I propose that the delayed spleen colony appearance in normal hosts is the result of developmental maturation of the primitive stem cell compartment that survives FU and is responsible for spleen colonies arising around day 14. This maturation, at least initially, occurs in the marrow and leads to the replenishment of the more differentiated CFU-S subsets ablated by FU, which are normally responsible for spleen colonies appearing earlier after transplantation.

scholarly journals Hematopoietic stem cells: effect of preirradiation, bleeding, and erythropoietin on thrombopoietic differentiation

Blood ◽  
1977 ◽  
Vol 49 (2) ◽  
pp. 253-261
Author(s):  
R Goodman ◽  
H Grate ◽  
E Hannon ◽  
S Hellman
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Proliferative Activity ◽  
Bone Marrow Cells ◽  
Cell Compartment ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem Cell Compartment ◽  
Cell Assays

A method of measuring differentiation of stem cells towards platelets is described using syngeneic bone marrow injected into lethally irradiated mice. Fourteen days after such injection, the platelet counts are found to be proportional to the number of bone marrow cells injected and can be used as a measure of platelet progenitors. Perturbation of the milieu in which the transplanted marrow is placed by host preirradiation, bleeding, or erythropoietin administration leads to enhanced thrombopoiesis. It has been shown previously that similar perturbation favors erythropoiesis at the expense of granulopoiesis. The data from these and other experiments appear to be consistent, with a model of the stem cell compartment as a continuum with proliferative activity increasing as commitment is restricted. These functions vary inversely with the capacity for self-renewal. The various stem cell assays measure different ranges of stem cells, but overlap within this continuum.

scholarly journals Effect of graft-versus-host disease on hematopoiesis after bone marrow transplantation in mice

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2773-2779
Author(s):  
PJ van Dijken ◽  
J Wimperis ◽  
JM Crawford ◽  
JL Ferrara
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cell Compartment ◽  
Host Disease ◽  
Murine Bone Marrow ◽  
Graft Versus Host ◽  
Stem Cell Compartment

We have examined the effect of graft-versus-host disease (GVHD) on the reconstitution of donor hematopoiesis in a murine bone marrow transplant (BMT) model of GVHD to minor histocompatibility antigens. GVHD had no effect on peripheral blood counts, which normalized by 1 month after BMT, and did not affect numbers of hematopoietic progenitors in the BM, which remained decreased in all transplant recipients. Donor stem cells (colony-forming unit-spleen day 8) and stem cell self-renewal remained low in all mice for 5 months after transplant, but GVHD further damaged the stem cell compartment. Peripheral counts 1 month after transplant were supported by increased numbers of stem cells in cycle and increased splenic hematopoiesis. However, GVHD altered the pattern of extramedullary hematopoiesis, causing dramatically decreased activity in the spleen and increased activity in the liver. We conclude that GVHD further decreases hematopoietic reserve and causes damage to the donor stem cell compartment during hematopoietic reconstitution after transplant, despite unaffected progenitor frequencies and peripheral blood counts.

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