scholarly journals Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1136-1141 ◽  
Author(s):  
K Bhalla ◽  
J Cole ◽  
W MacLaughlin ◽  
M Baker ◽  
Z Arlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Prostaglandin E1 ◽  
S Phase ◽  
In Vitro Growth ◽  
Inhibitory Effects ◽  
Initial Exposure ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract We have examined the effect of supraphysiologic concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) on the in vitro growth of normal (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. Bone marrow samples obtained from 34 consecutive patients undergoing routine diagnostic bone marrow aspirations for nonmalignant hematologic disorders exhibited nearly a twofold increment in CFU-GM when continuously cultured in the presence of 10(-4) mol/L dCyd. Higher dCyd concentrations were associated with a smaller degree of enhancement of colony formation. In contrast, the growth of leukemic blast progenitors obtained from patients with acute nonlymphocytic leukemia were not enhanced by any of the dCyd concentrations tested. Coadministration of 10(-3) mol/L tetrahydrouridine (THU), a cytidine deaminase inhibitor, failed to alter the relative inability of dCyd to enhance L-CFU colony growth. The stimulatory effect of dCyd on normal CFU-GM was not mediated by the adherent mononuclear cell population of the marrow, nor was it restricted to the subpopulation of CFU-GM in S phase at the time of initial exposure. Moreover, treatment of normal bone marrow cells with dCyd at concentrations ranging from 10(-6) to 5 X 10(-3) mol/L for 24 hours had only a minor effect on the fraction of CFU-GM in S phase. Coadministration of 10(-4) mol/L dCyd was able to reverse the inhibitory effects of several putative regulators of normal myelopoiesis, including leukemia inhibitory activity (LIA), acidic isoferritins (AIF), and prostaglandin E1 (PGE1). Leukemic myeloblasts exposed to 10(-4) mol/L dCyd exhibited substantial expansion of intracellular pools of dCyd triphosphate (dCTP), demonstrating that inability to metabolize dCyd could not be solely responsible for the absence of growth potentiation in these cells. These studies suggest that supraphysiologic concentrations of dCyd may confer a selective in vitro growth advantage upon normal v leukemic myeloid progenitor cells, and may free the former from the inhibitory effects of several potential negative regulators of myelopoiesis.

scholarly journals Deoxycytidine stimulates the in vitro growth of normal CFU-GM and reverses the negative regulatory effects of acidic isoferritin and prostaglandin E1

Blood ◽  
1986 ◽  
Vol 68 (5) ◽  
pp. 1136-1141
Author(s):  
K Bhalla ◽  
J Cole ◽  
W MacLaughlin ◽  
M Baker ◽  
Z Arlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Prostaglandin E1 ◽  
S Phase ◽  
In Vitro Growth ◽  
Inhibitory Effects ◽  
Initial Exposure ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

We have examined the effect of supraphysiologic concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) on the in vitro growth of normal (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. Bone marrow samples obtained from 34 consecutive patients undergoing routine diagnostic bone marrow aspirations for nonmalignant hematologic disorders exhibited nearly a twofold increment in CFU-GM when continuously cultured in the presence of 10(-4) mol/L dCyd. Higher dCyd concentrations were associated with a smaller degree of enhancement of colony formation. In contrast, the growth of leukemic blast progenitors obtained from patients with acute nonlymphocytic leukemia were not enhanced by any of the dCyd concentrations tested. Coadministration of 10(-3) mol/L tetrahydrouridine (THU), a cytidine deaminase inhibitor, failed to alter the relative inability of dCyd to enhance L-CFU colony growth. The stimulatory effect of dCyd on normal CFU-GM was not mediated by the adherent mononuclear cell population of the marrow, nor was it restricted to the subpopulation of CFU-GM in S phase at the time of initial exposure. Moreover, treatment of normal bone marrow cells with dCyd at concentrations ranging from 10(-6) to 5 X 10(-3) mol/L for 24 hours had only a minor effect on the fraction of CFU-GM in S phase. Coadministration of 10(-4) mol/L dCyd was able to reverse the inhibitory effects of several putative regulators of normal myelopoiesis, including leukemia inhibitory activity (LIA), acidic isoferritins (AIF), and prostaglandin E1 (PGE1). Leukemic myeloblasts exposed to 10(-4) mol/L dCyd exhibited substantial expansion of intracellular pools of dCyd triphosphate (dCTP), demonstrating that inability to metabolize dCyd could not be solely responsible for the absence of growth potentiation in these cells. These studies suggest that supraphysiologic concentrations of dCyd may confer a selective in vitro growth advantage upon normal v leukemic myeloid progenitor cells, and may free the former from the inhibitory effects of several potential negative regulators of myelopoiesis.

The combined effects of Il-3, GM-CSF and G-CSF on the in vitro growth of myelodysplastic myeloid progenitor cells

1990 ◽  
Vol 14 (11-12) ◽  
pp. 1019-1025 ◽  
Author(s):  
Martin R. Schipperus ◽  
Pieter Sonneveld ◽  
Jan Lindemans ◽  
Nel Vink ◽  
Margreet Vlastuin ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Combined Effects ◽  
In Vitro Growth ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Altered Development and Cytokine Responses of Myeloid Progenitors in the Absence of Transcription Factor, Interferon Consensus Sequence Binding Protein

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3764-3771 ◽  
Author(s):  
Marina Scheller ◽  
John Foerster ◽  
Clare M. Heyworth ◽  
Jeffrey F. Waring ◽  
Jürgen Löhler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Binding Protein ◽  
Marrow Cell ◽  
Consensus Sequence ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP−/− mice, we investigated the growth, differentiation, and leukemogenic potential of ICSBP−/−myeloid progenitor cells in vitro, as well as by cell-transfers in vivo. We report that adult bone marrow, as well as fetal liver of ICSBP-deficient mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF in vitro. In contrast, their response to M-CSF is strongly reduced and, surprisingly, ICSBP−/− colonies formed in the presence of M-CSF are mostly of granulocytic morphology. This disproportional differentiation toward cells of the granulocytic lineage in vitro parallels the expansion of granulocytes in ICSBP−/− mice and correlates with a 4-fold reduction of M-CSF receptor expressing cells in bone marrow. Cell transfer studies showed an intrinsic leukemogenic potential and long-term reconstitution capability of ICSBP−/− progenitors. Further experiments demonstrated strongly reduced adhesion of colony-forming cells from ICSBP−/− bone marrow to fibronectin. In summary, ICSBP−/− myeloid progenitor cells share several abnormal features with CML progenitors, suggesting that the distal parts of signaling pathways of these two disorders are overlapping.

scholarly journals Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2583-2587 ◽  
Author(s):  
AL Petzer ◽  
R Bilgeri ◽  
U Zilian ◽  
M Haun ◽  
FH Geisen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
T Lymphocyte ◽  
Human Lymphocytes ◽  
Maturation Stage ◽  
Dependent Manner ◽  
Myeloid Progenitor ◽  
Marked Inhibition ◽  
Myeloid Progenitor Cells

Abstract Previous studies have shown that 2-chloro-2′-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony- forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

scholarly journals ANTIGENIC DIFFERENCES BETWEEN HEMOPOIETIC STEM CELLS AND MYELOID PROGENITORS

1974 ◽  
Vol 139 (6) ◽  
pp. 1621-1627 ◽  
Author(s):  
Gerrit J. Van den Engh ◽  
Edward S. Golub
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Myeloid Cell ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Myeloid Progenitors

Bone marrow contains pluripotent stem cells which give rise to colonies when injected into irradiated syngenic hosts as well as more differentiated progenitor cells of the myeloid cell which are able to form colonies in vitro. Antisera against brain is known to contain antistem cell antibody. The present experiments were designed to determine if the myeloid progenitor cell still expresses the stem cell antigen. Bone marrow cells were treated with antibrain antiserum plus complement and then survival of stem cells was determined by injection into irradiated hosts. Survival of myeloid progenitor cells was determined by culturing the cells in vitro. It was found that stem cells were eliminated by the antiserum but that myeloid progenitors were not. Inefficient in vitro lysis was ruled out as the reason for this difference since in vitro colonies were not reduced when the cells were treated with anti-immunoglobulin or after passage through an irradiated host. In the differentiation from stem cell to myeloid progenitor there is an associated surface antigen change.

STAT3 Deletion after Birth Results in Marked Decreases in Absolute Numbers and Cell Cycling Status of Marrow and Spleen Myeloid Progenitor Cells, and STAT3 Is a Critical Molecule in Mediating Synergistically Stimulated Progenitor Cell Proliferation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1346-1346
Author(s):  
Hal E. Broxmeyer ◽  
Scott Cooper ◽  
Giao Hangoc ◽  
Wenjun Zhang ◽  
Akira Moh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Mouse Model ◽  
Progenitor Cells ◽  
Ample Evidence ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract STAT3 is an important transcription factor involved in mediating intracellular signals initiated at the cell membrane by cytokines and growth factors. There is ample evidence that STAT3 acts as a positive regulator of cell growth, but most of this information derives from studies done with isolated cells in vitro. Because functional deletion of STAT3 in mice is lethal, it was difficult to evaluate a role for STAT3 in mediating hematopoietic effects in vivo in mice after birth. To address this problem, a unique strain of mice was developed with tissue specific disruption of STAT3 in bone marrow and hematopoietic cells (Welte et.al. PNAS100: 1879, 2003). The availability of this conditional STAT3 −/− mouse model demonstrated a critical role for STAT3 in innate immunity. We have now utilized this conditional STAT3 −/− mouse model to evaluate a role for STAT3 in hematopoiesis after birth, with the hypothesis that STAT3 would be one critical factor involved in the proliferation of myeloid progenitor cells (MPC: CFU-GM, BFU-E, CFU-GEMM) in bone marrow and spleen. STAT3 −/− and their littermate control mice were evaluated at 4 weeks of age. STAT3 −/− mice manifested 40–44% decreases in absolute numbers of nucleated cells in the marrow (femur) and spleen. This was associated with decreased absolute numbers of CFU-GM (70%), BFU-E (70%) and CFU-GEMM (50%) per femur and CFU-GM (50%), BFU-E (30%), and CFU-GEMM (50%) per spleen for these MPC which are responsive in vitro to stimulation of colony formation by the combination of EPO, SCF, TPO and growth factors in PWMSCM. Moreover, MPC from STAT3 −/− mice were in a slow or non cycling state (0–4% MPC in S-phase) in marrow and spleen compared to 50–60% marrow and 32–48% spleen MPC from +/+ mice being in active cell cycle. There were also large decreases per femur in STAT3 −/− mice in terms of GM-CSF-, IL-3-, M-CSF-, GM-CSF plus SCF-, GM-CSF plus Flt3 ligand (FL)-, IL-3 plus SCF-, IL-3 plus FL-, M-CSF plus SCF-, and M-CSF plus FL- responsive CFU-GM. These decreases may in part reflect the finding that CFU-GM from STAT3 −/− mice did not respond to the synergistic proliferation effects of GM-CSF, IL-3, or M-CSF, each in combination with either SCF or FL. At best these cytokine combinations resulted in additive proliferative effects on MPC from marrow of STAT3 −/− mice in contrast to CFU-GM from +/+ mouse marrow where the effects were clearly synergistic. In terms of survival of MPC, there were no apparent differences between the survival of MPC from STAT3 −/− and +/+ mice after withdrawal of growth factors in vitro and their delayed addition to the cell cultures. MPC from STAT3 −/− and +/+ marrow responded similarly to the survival enhancing effects in vitro of SDF-1/CXCL12. Our results demonstrate that after birth STAT3 acts as a positive mediator of the proliferation of MPC in vivo, and STAT3 is a critical mediator of the synergistic proliferation effects of cytokines on MPC.

Altered Development and Cytokine Responses of Myeloid Progenitors in the Absence of Transcription Factor, Interferon Consensus Sequence Binding Protein

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3764-3771 ◽  
Author(s):  
Marina Scheller ◽  
John Foerster ◽  
Clare M. Heyworth ◽  
Jeffrey F. Waring ◽  
Jürgen Löhler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Binding Protein ◽  
Marrow Cell ◽  
Consensus Sequence ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP−/− mice, we investigated the growth, differentiation, and leukemogenic potential of ICSBP−/−myeloid progenitor cells in vitro, as well as by cell-transfers in vivo. We report that adult bone marrow, as well as fetal liver of ICSBP-deficient mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF in vitro. In contrast, their response to M-CSF is strongly reduced and, surprisingly, ICSBP−/− colonies formed in the presence of M-CSF are mostly of granulocytic morphology. This disproportional differentiation toward cells of the granulocytic lineage in vitro parallels the expansion of granulocytes in ICSBP−/− mice and correlates with a 4-fold reduction of M-CSF receptor expressing cells in bone marrow. Cell transfer studies showed an intrinsic leukemogenic potential and long-term reconstitution capability of ICSBP−/− progenitors. Further experiments demonstrated strongly reduced adhesion of colony-forming cells from ICSBP−/− bone marrow to fibronectin. In summary, ICSBP−/− myeloid progenitor cells share several abnormal features with CML progenitors, suggesting that the distal parts of signaling pathways of these two disorders are overlapping.

scholarly journals Deoxycytidine preferentially protects normal versus leukemic myeloid progenitor cells from cytosine arabinoside-mediated cytotoxicity

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 568-571 ◽  
Author(s):  
K Bhalla ◽  
W MacLaughlin ◽  
J Cole ◽  
Z Arlin ◽  
M Baker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Colony Formation ◽  
Mononuclear Cells ◽  
Leukemic Cells ◽  
High Dose ◽  
Bone Marrow Mononuclear Cells ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract We examined the ability of high concentrations of the naturally occurring nucleoside deoxycytidine (dCyd) to reverse the cytotoxicity of high (eg, greater than or equal to 10(-5) mol/L) concentrations of 1- B-D arabinofuranosylcytosine (Ara-C) toward normal (CFU-GM) and leukemic myeloid progenitor cells (L-CFU). Leukemic myeloblasts from patients with acute nonlymphocytic leukemia (ANLL) and normal human bone marrow mononuclear cells were cultured in soft agar in the continuous presence of 10(-5) to 5 X 10(-5) mol/L of Ara-C together with dCyd (10(-4) to 5 X 10(-3) mol/L). Administration of 10(-5) mol/L of Ara-C alone eradicated colony formation in all samples tested. Coadministration of 10(-3) mol/L of dCyd restored 72.2% of control colony formation for CFU-GM, but only 10.9% for L-CFU. When higher concentrations of Ara-C (eg, 5 X 10(-5) mol/L) were administered, dCyd- mediated protection toward CFU-GM decreased, but remained significantly greater than that observed for L-CFU. Incubation with 10(-3) mol/L of dCyd reduced the 4-hour intracellular accumulation of the triphosphate derivative of Ara-C (Ara-CTP) in both normal and leukemic cells by greater than 98%; under identical conditions, a significant expansion of the intracellular of the triphosphate derivative of dCyd (dCTP) pools was observed in normal bone marrow mononuclear cells but not in leukemic blasts. This finding was associated with a greater reduction in Ara-C DNA incorporation in normal elements. These in vitro studies suggest that dCyd may preferentially protect normal v leukemic myeloid progenitor cells from the lethal actions of high-dose Ara-C.

scholarly journals Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2583-2587 ◽  
Author(s):  
AL Petzer ◽  
R Bilgeri ◽  
U Zilian ◽  
M Haun ◽  
FH Geisen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
T Lymphocyte ◽  
Human Lymphocytes ◽  
Maturation Stage ◽  
Dependent Manner ◽  
Myeloid Progenitor ◽  
Marked Inhibition ◽  
Myeloid Progenitor Cells

Previous studies have shown that 2-chloro-2′-deoxyadenosine (CdA) is markedly toxic to normal and malignant human lymphocytes in vitro and in vivo. Recent clinical trials have shown that CdA is a very promising drug for the treatment of lymphoid malignancies. The present investigations were designed to test the effect of CdA on the in vitro clonal growth of both myeloid progenitors and T-lymphocyte colony- forming cells (CFU-TL) obtained from normal human bone marrow and peripheral blood. Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were used for our investigations. The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming cells in a dose-dependent manner, correlating with maturation stage in that the immature progenitor cells are more sensitive to this drug. Furthermore, our studies suggest that a sequence of metabolic events previously described for lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of 48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to be high in lymphocytes, but low in granulocytes. However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that other factors such as modulation of the effect of CdA by the ambient levels of other deoxynucleosides might influence the apparent sensitivity of myeloid cells.

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