scholarly journals The effects of three recombinant growth factors, IL-3, GM-CSF, and G- CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 657-663 ◽  
Author(s):  
J Miyauchi ◽  
CA Kelleher ◽  
YC Yang ◽  
GG Wong ◽  
SC Clark ◽  
...  
Keyword(s):  
Growth Factors ◽  
Acute Myeloblastic Leukemia ◽  
Colony Stimulating Factor ◽  
Short Term ◽  
Gm Csf ◽  
Bladder Cell ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The blast stem cells of acute myeloblastic leukemia (AML) respond in cell culture to growth factors by both self-renewal and terminal divisions. Both of these functions have been shown to be stimulated by the recombinant growth factors granulocyte-macrophage colony- stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). In this paper, recombinant gibbon interleukin-3 (IL-3), homologous to human IL-3, was tested on blast cells and compared with the effects of GM-CSF, G-CSF, and medium conditioned by the bladder cell line 5637 (5637-CM). We found that IL-3 was an effective stimulator of blast renewal and terminal divisions. However, great patient-to-patient variation was found. A graphic method of presenting complex comparisons between growth factors is also included.

scholarly journals The effects of three recombinant growth factors, IL-3, GM-CSF, and G- CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 657-663 ◽  
Author(s):  
J Miyauchi ◽  
CA Kelleher ◽  
YC Yang ◽  
GG Wong ◽  
SC Clark ◽  
...  
Keyword(s):  
Growth Factors ◽  
Acute Myeloblastic Leukemia ◽  
Colony Stimulating Factor ◽  
Short Term ◽  
Gm Csf ◽  
Bladder Cell ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The blast stem cells of acute myeloblastic leukemia (AML) respond in cell culture to growth factors by both self-renewal and terminal divisions. Both of these functions have been shown to be stimulated by the recombinant growth factors granulocyte-macrophage colony- stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). In this paper, recombinant gibbon interleukin-3 (IL-3), homologous to human IL-3, was tested on blast cells and compared with the effects of GM-CSF, G-CSF, and medium conditioned by the bladder cell line 5637 (5637-CM). We found that IL-3 was an effective stimulator of blast renewal and terminal divisions. However, great patient-to-patient variation was found. A graphic method of presenting complex comparisons between growth factors is also included.

scholarly journals Effects of recombinant GM-CSF on the blast cells of acute myeloblastic leukemia

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 313-316 ◽  
Author(s):  
T Hoang ◽  
N Nara ◽  
G Wong ◽  
S Clark ◽  
MD Minden ◽  
...  
Keyword(s):  
Suspension Culture ◽  
Adherent Cells ◽  
Colony Stimulating Factor ◽  
Response Curves ◽  
Self Renewal ◽  
Gm Csf ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The effects of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) were compared to those of media conditioned by the continuous bladder carcinoma line, HTB9 (HTB9-CM), using three criteria. First, both GM-CSF and HTB9-CM stimulated blast colony formation in methylcellulose cultures, patient-to-patient variations were seen in the dose-response curves, and GM-CSF was effective, but less so that HTB9-CM. Second, GM-CSF also enhanced growth of blast progenitors in suspension culture, indicating its capacity to support self-renewal. GM-CSF was as effective as HTB9-CM in the production of adherent cells during the growth of blast cells in suspension, a finding that is interpreted to mean that GM-CSF also supports postdeterministic events in blast differentiation. Finally, colonies growing in the presence of GM-CSF were not phenotypically different than those stimulated by HTB9-CM.

scholarly journals Differential and synergistic effects of human granulocyte-macrophage colony-stimulating factor and human granulocyte colony-stimulating factor on hematopoiesis in human long-term marrow cultures

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 493-499 ◽  
Author(s):  
DE Hogge ◽  
JD Cashman ◽  
RK Humphries ◽  
CJ Eaves
Keyword(s):  
Growth Factors ◽  
Synergistic Effects ◽  
S Phase ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Single Addition ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The ability of granulocyte-macrophage colony-stimulating factor (GM- CSF) and G-CSF to influence hematopoiesis in long-term cultures (LTC) of human marrow was studied by cocultivating light density normal human marrow cells with human marrow fibroblast feeders engineered by retroviral infection to constitutively produce one of these growth factors. Feeders producing stable levels of 4 ng/mL GM-CSF or 20 ng/mL G-CSF doubled the output of mature nonadherent cells. The numbers of both colony forming unit-GM (CFU-GM) and erythroid burst forming unit (BFU-E) in the G-CSF LTC were also increased (twofold and fourfold, respectively, after 5 weeks in culture), but this effect was not seen with the GM-CSF feeders. At the time of the weekly half medium change 3H-thymidine suicide assays showed primitive adherent layer progenitors in LTC to be quiescent in both the control and GM-CSF cultures. In contrast, in the G-CSF cultures, a high proportion of primitive progenitors were in S-phase. A single addition of either recombinant GM- CSF or G-CSF to LTC in doses as high as 80 ng/mL and 150 ng/mL, respectively, failed to induce primitive progenitor cycling. However, three sequential daily additions of 150 ng/mL G-CSF did stimulate primitive progenitors to enter S-phase and a single addition of 5 or 12.5 ng/mL of G-CSF together with 10 ng/mL GM-CSF was able to elicit the same effect. Thus, selective elevation of G-CSF in human LTC stimulates proliferation of primitive clonogenic progenitors, which may then proceed through to the terminal stages of granulopoiesis. In contrast, the effects of GM-CSF in this system appear limited to terminally differentiating granulopoietic cells. However, when both GM- CSF and G-CSF are provided together, otherwise biologically inactive doses show strong stimulatory activity. These findings suggest that the production of both of these growth factors by normal stromal cells may contribute to the support and proliferation of hematopoietic cells, not only in LTC, but also in the microenvironment of the marrow in vivo.

scholarly journals A comparison of treatment of canine cyclic hematopoiesis with recombinant human granulocyte-macrophage colony-stimulating factor (GM- CSF), G-CSF interleukin-3, and canine G-CSF

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 523-532 ◽  
Author(s):  
WP Hammond ◽  
TC Boone ◽  
RE Donahue ◽  
LM Souza ◽  
DC Dale
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Cell Counts ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Cyclic Hematopoiesis ◽  
Stimulating Factor

Cyclic hematopoiesis in gray collie dogs is a stem cell disease in which abnormal regulation of cell production in the bone marrow causes cyclic fluctuations of blood cell counts. In vitro studies demonstrated that recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and granulocyte colony stimulating factor (G-CSF) all stimulated increases in colony formation by canine bone marrow progenitor cells. Based on these results, gray collie dogs were then treated with recombinant human (rh) GM-CSF, IL-3, or G-CSF subcutaneously to test the hypothesis that pharmacologic doses of one of these hematopoietic growth factors could alter cyclic production of cells. When recombinant canine G-CSF became available, it was tested over a range of doses. In vivo rhIL-3 had no effect on the recurrent neutropenia but was associated with eosinophilia, rhGM-CSF caused neutrophilia and eosinophilia but cycling of hematopoiesis persisted. However, rhG-CSF caused neutrophilia, prevented the recurrent neutropenia and, in the two animals not developing antibodies to rhG- CSF, obliterated periodic fluctuation of monocyte, eosinophil, reticulocyte, and platelet counts. Recombinant canine G-CSF increased the nadir neutrophil counts and amplitude of fluctuations at low doses (1 micrograms/kg/d) and eliminated all cycling of cell counts at high doses (5 and 10 micrograms/kg/d). These data suggest significant differences in the actions of these growth factors and imply a critical role for G-CSF in the homeostatic regulation of hematopoiesis.

scholarly journals Effects of granulocyte-macrophage colony-stimulating factor and erythropoietin on leukemic erythroid colony formation in human early erythroblastic leukemias

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 965-973 ◽  
Author(s):  
MT Mitjavila ◽  
JL Villeval ◽  
P Cramer ◽  
A Henri ◽  
J Gasson ◽  
...  
Keyword(s):  
Growth Factors ◽  
Plating Efficiency ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Erythroid Progenitors ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Autonomous Growth

Abstract Erythroid colonies from five patients with an early erythroblastic leukemia were obtained in “serum-free” cultures in the presence or absence of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and homogeneous native erythropoietin (Epo). Erythroid colonies with abnormal morphology and karyotype could be grown in different culture conditions. Their erythroid nature was ascertained by the presence of carbonic anhydrase I and glycophorin A. Leukemic erythroid progenitors strongly differed from normal progenitors in that spontaneous colonies were always obtained, sometimes with an extremely high plating efficiency (up to 5.7%). Colonies were found to be autonomous from exogenous hematopoietic growth factors because they were still obtained with a high plating efficiency at an average of one cell per culture in the absence of any added growth factor. No evidence for an autocrine secretion of Epo or GM-CSF emerged because Epo or GM- CSF could not be detected by biologic or radioimmunologic assays from the culture supernatant or cellular extracts of the leukemic cells and that Epo or GM-CSF antibodies did not block autonomous growth. In all cases, however, hematopoietic growth factors increased the plating efficiency of the abnormal erythroid progenitors. In the two “de novo” leukemias, leukemic erythroid progenitors responded primarily to Epo, whereas in the three other patients' (chronic myeloid leukemia) blast crisis they responded maximally to GM-CSF plus Epo. Recombinant erythroid-potentiating activity had no effect in any of these cases. These results suggest that the leukemic erythroid clonogenic cells arise from expansion of erythroid progenitors at different levels of differentiation (ie, CFU-E or BFU-E, depending upon the disease) and that autonomous growth is not related to a secretion of Epo or GM-CSF.

scholarly journals Interleukin-6 enhances growth factor-dependent proliferation of the blast cells of acute myeloblastic leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 823-826 ◽  
Author(s):  
T Hoang ◽  
A Haman ◽  
O Goncalves ◽  
GG Wong ◽  
SC Clark
Keyword(s):  
Interleukin 6 ◽  
Bone Marrow Cells ◽  
Acute Myeloblastic Leukemia ◽  
Gm Csf ◽  
Normal Bone ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

Abstract The effects of recombinant interleukin-6 (IL-6) on the proliferation of blast precursors present in the peripheral blood of patients with acute myeloblastic leukemia (AML) was investigated. IL-6 had little effect by itself; however, it synergized with granulocyte macrophage colony- stimulating factor (GM-CSF) and interleukin-3 (IL-3) in the stimulation of AML blast colony formation. Responsiveness of blast progenitors to IL-6 was heterogeneous. On normal bone marrow cells the same synergy was observed on granulocyte and monocyte precursors (GM-CFC), while there was no significant effect on erythroid and multipotential precursors.

scholarly journals Structure and expression of genes of GM-CSF and G-CSF in blast cells from patients with acute myeloblastic leukemia

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 204-208 ◽  
Author(s):  
GY Cheng ◽  
CA Kelleher ◽  
J Miyauchi ◽  
C Wang ◽  
G Wong ◽  
...  
Keyword(s):  
Genomic Organization ◽  
Acute Myeloblastic Leukemia ◽  
Leukemic Cells ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Expression Of Genes ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The hematopoietic growth factors granulocyte/macrophage colony- stimulating factor (GM-CSF) and G-CSF, available as recombinant products, stimulate the growth in culture of blasts from patients with acute myeloblastic leukemia (AML). We used cDNA probes for each gene to study the genomic organization in blast cells of 22 patients and expression in the blast cells of 18 patients. Alteration in the structure of G-CSF (two instances) and GM-CSF (two instances) was found. In two patients in whom it was possible to study DNA from bone marrow obtained at remission, the new bands detected in the leukemic cells were not found. Fifteen of 18 patients showed no RNA expression of either growth factor. Both patients with GM-CSF abnormalities as seen by Southern analysis expressed an abnormally large GM-CSF message but no G-CSF messages. One patient with an abnormal Southern pattern with G-CSF expressed normal-sized G-CSF and GM-CSF messages. The biologic significance of these findings remains to be determined. Nonetheless, the abnormal Southern patterns may prove to be useful clonal markers in the study of AML.

scholarly journals Coordinate secretion of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor by the blast cells of acute myeloblastic leukemia: role of interleukin-1 as an endogenous inducer

Blood ◽  
1990 ◽  
Vol 76 (8) ◽  
pp. 1481-1489 ◽  
Author(s):  
JC Rodriguez-Cimadevilla ◽  
V Beauchemin ◽  
L Villeneuve ◽  
F Letendre ◽  
A Shaw ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Interleukin 1 ◽  
Acute Myeloblastic Leukemia ◽  
Colony Stimulating Factor ◽  
Autocrine Growth ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
High Production ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Acute myeloblastic leukemia (AML) blasts have been shown to produce a variety of cytokines in culture such as interleukin-1 (IL-1), IL-6, granulocyte-, macrophage-, and granulocyte-macrophage colony- stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF alpha). Using two sensitive and specific enzyme-linked immunosorbent assays for IL-1 beta and GM-CSF, we document in the present study that the production of the two cytokines by AML blasts in culture is coordinated. First, we observe a striking correlation between the levels of GM-CSF and IL-1 beta released by the cells. Thus, a high production of IL-1 beta is always concordant with a high production of GM-CSF and, conversely, low production of IL-1 beta is concordant with low levels of GM-CSF. Second, neutralization of intrinsic IL-1 using antibodies that are specific for IL-1 alpha and -1 beta suppresses the release of GM-CSF by the cells. Third, neutralization of the endogenous source of IL-1 also results in an abrogation of GM-CSF mRNA. Fourth, the production of both IL-1 beta and GM-CSF is up-regulated by exposing AML blasts to an exogenous source of IL-1, suggesting a positive regulation of autocrine growth factor production. Taken together, our results indicate that GM-CSF production by AML blasts is mediated by endogenously produced IL-1. Both IL-1 beta and -1 alpha are produced by AML blasts, although IL-1 beta appears to be more abundant. Spontaneous colony formation by AML blasts is abrogated by the addition of neutralizing antibodies against IL-1 beta and GM-CSF, whereas each antibody alone has little effect on blast proliferation. Taken together, our results are consistent with the view that the production of IL-1 beta by AML blasts supports autocrine growth in culture, through induction of CSFs or other cytokines that stimulate blast proliferation.

scholarly journals Interleukin-6 enhances growth factor-dependent proliferation of the blast cells of acute myeloblastic leukemia

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 823-826
Author(s):  
T Hoang ◽  
A Haman ◽  
O Goncalves ◽  
GG Wong ◽  
SC Clark
Keyword(s):  
Interleukin 6 ◽  
Bone Marrow Cells ◽  
Acute Myeloblastic Leukemia ◽  
Gm Csf ◽  
Normal Bone ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Stimulation Of

The effects of recombinant interleukin-6 (IL-6) on the proliferation of blast precursors present in the peripheral blood of patients with acute myeloblastic leukemia (AML) was investigated. IL-6 had little effect by itself; however, it synergized with granulocyte macrophage colony- stimulating factor (GM-CSF) and interleukin-3 (IL-3) in the stimulation of AML blast colony formation. Responsiveness of blast progenitors to IL-6 was heterogeneous. On normal bone marrow cells the same synergy was observed on granulocyte and monocyte precursors (GM-CFC), while there was no significant effect on erythroid and multipotential precursors.

scholarly journals Differential and synergistic effects of human granulocyte-macrophage colony-stimulating factor and human granulocyte colony-stimulating factor on hematopoiesis in human long-term marrow cultures

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 493-499 ◽  
Author(s):  
DE Hogge ◽  
JD Cashman ◽  
RK Humphries ◽  
CJ Eaves
Keyword(s):  
Growth Factors ◽  
Synergistic Effects ◽  
S Phase ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Single Addition ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The ability of granulocyte-macrophage colony-stimulating factor (GM- CSF) and G-CSF to influence hematopoiesis in long-term cultures (LTC) of human marrow was studied by cocultivating light density normal human marrow cells with human marrow fibroblast feeders engineered by retroviral infection to constitutively produce one of these growth factors. Feeders producing stable levels of 4 ng/mL GM-CSF or 20 ng/mL G-CSF doubled the output of mature nonadherent cells. The numbers of both colony forming unit-GM (CFU-GM) and erythroid burst forming unit (BFU-E) in the G-CSF LTC were also increased (twofold and fourfold, respectively, after 5 weeks in culture), but this effect was not seen with the GM-CSF feeders. At the time of the weekly half medium change 3H-thymidine suicide assays showed primitive adherent layer progenitors in LTC to be quiescent in both the control and GM-CSF cultures. In contrast, in the G-CSF cultures, a high proportion of primitive progenitors were in S-phase. A single addition of either recombinant GM- CSF or G-CSF to LTC in doses as high as 80 ng/mL and 150 ng/mL, respectively, failed to induce primitive progenitor cycling. However, three sequential daily additions of 150 ng/mL G-CSF did stimulate primitive progenitors to enter S-phase and a single addition of 5 or 12.5 ng/mL of G-CSF together with 10 ng/mL GM-CSF was able to elicit the same effect. Thus, selective elevation of G-CSF in human LTC stimulates proliferation of primitive clonogenic progenitors, which may then proceed through to the terminal stages of granulopoiesis. In contrast, the effects of GM-CSF in this system appear limited to terminally differentiating granulopoietic cells. However, when both GM- CSF and G-CSF are provided together, otherwise biologically inactive doses show strong stimulatory activity. These findings suggest that the production of both of these growth factors by normal stromal cells may contribute to the support and proliferation of hematopoietic cells, not only in LTC, but also in the microenvironment of the marrow in vivo.

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