Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor Increases DNA Polymerase Activity in Acute Myeloid Leukemia Blasts In Vitro and In Vivo

1992 ◽  
pp. 321-328
Author(s):  
C. Reuter ◽  
Ulrike Auf der Landwehr ◽  
M. Zühlsdorf ◽  
C. Busemann ◽  
B. Wörmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dna Polymerase ◽  
Polymerase Activity ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

scholarly journals Therapeutic Blockade of Macrophage Colony Stimulating Factor (CSF-1) Delays AML Progression in Mice In Vivo

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2835-2835
Author(s):  
Sal Lee Goh ◽  
Jean-Pierre Levesque ◽  
Allison R Petitt ◽  
Valarie Barbier ◽  
Ingrid G Winkler
Keyword(s):  
Colony Stimulating Factor ◽  
Tumour Burden ◽  
Therapeutic Blockade ◽  
Stem And Progenitor Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Macrophage colony-stimulating factor (M-CSF or CSF-1) plays a role in regulating innate immune responses promoting macrophage growth and differentiation. We hypothesized CSF-1 may also play a role in growth and progression of Acute Myeloid Leukaemia (AML). The aim of this study is to investigate the role of CSF-1 in survival and chemo-resistance of leukaemia stem and progenitor cells (LSPC). We further hypothesized that blocking CSF-1R signalling in LSPC may dampen leukaemia survival in vitro and delay leukaemia progression in vivo. AML was induced in mice by injecting murine Haematopoietic Stem and Progenitor Cells (HSPC) transduced with either MLL-AF9 or AML1- ETO fusion oncogenes for the development of either monomyelocytic or granulocytic leukaemia respectively. We found CSF-1R, the main receptor for CSF-1, was expressed on these acute myeloid leukaemia cells, thus it is possible that CSF-1 provide supportive microenvironment for leukemic growth. To identify whether CSF-1 in the bone marrow (BM) niche is essential for growth of malignant LSPC, we harvested normal or- leukaemic blasts from BM for in vitro studies using Long-Term Culture-Initiating-Cell (LT-CIC) assays. In these assays AML LSPC or normal HSPC cells were co-cultured with mesenchymal stromal cells (MSC) from either wildtype mice (MSC that produce CSF-1) or MSC from OP/OP mice (unable to produce functional CSF-1). We found normal (wild-type) HSPC were able to proliferate, survive and produce LT-CIC in the absence of niche-provided CSF-1, however AML blasts could not, unless rescued by addition of recombinant CSF-1 (100 ng/mL) in vitro. Together these data suggest CSF-1 signalling may be critical for AML LSPC but not normal HSPC. Next we investigated in mice whether therapeutic CSF-1 blockade could similarly dampen AML survival or progression in vivo. Cohorts of mice were injected with luciferase-expressing monomyelocytic (MLL-AF9) BM leukaemic blasts, then 7 days later administered the small molecule CSF-1 antagonist (GW2580, 160mg/kg daily for 10 days) or vehicle control. Leukaemia progression was tracked by biweekly bioluminescence and testbleeds for appearance of GFP+ leukaemia blasts in blood. We found therapeutic blockade of CSF-1 significantly reduced tumour burden in these mice by both bioluminescence and testbleed analysis. Mice were also monitored for duration of survival. As anticipated by the observed reduction in leukaemia burden, therapeutic CSF-1 blockade also significantly extended the duration of overall mouse survival (P<0.005, n= 8 mice/ group). Together these studies suggest therapeutic CSF-1 blockade may show promise as an adjunct therapy to help reduce tumour burden and improve success of AML leukaemia therapies. Disclosures Winkler: GlycoMimetics: Research Funding.

scholarly journals The Chemotactic Cytokine Eotaxin Acts as a Granulocyte-Macrophage Colony-Stimulating Factor During Lung Inflammation

Blood ◽  
1998 ◽  
Vol 91 (6) ◽  
pp. 1909-1916 ◽  
Author(s):  
Amnon Peled ◽  
Jose Angel Gonzalo ◽  
Clare Lloyd ◽  
Jose-Carlos Gutierrez-Ramos
Keyword(s):  
Neutralizing Antibodies ◽  
Allergic Inflammation ◽  
Colony Stimulating Factor ◽  
Chemotactic Cytokine ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Myeloid Progenitors

Abstract During inflammatory processes, inflamed tissues signal the bone marrow (BM) to produce more mature leukocytes in ways that are not yet understood. We report here that, during the development of lung allergic inflammation, the administration of neutralizing antibodies to the chemotactic cytokine, Eotaxin, prevented the increase in the number of myeloid progenitors produced in the BM, therefore reducing the output of mature myeloid cells from BM. Conversely, the in vivo administration of Eotaxin increased the number of myeloid progenitors present in the BM. Furthermore, we found that, in vitro, Eotaxin is a colony-stimulating factor for granulocytes and macrophages. Eotaxin activity synergized with stem cell factor but not with interleukin-3 or granulocyte-macrophage colony-stimulating factor and was inhibited bypertussis toxin. We report also that CCR-3, the receptor for Eotaxin, was expressed by hematopoietic progenitors (HP). Thus, during inflammation, Eotaxin acts in a paracrine way to shift the differentiation of BM HP towards the myeloid lineage.

scholarly journals Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse

Blood ◽  
1991 ◽  
Vol 78 (5) ◽  
pp. 1190-1197 ◽  
Author(s):  
T Buchner ◽  
W Hiddemann ◽  
M Koenigsmann ◽  
M Zuhlsdorf ◽  
B Wormann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract To reduce critical neutropenia after chemotherapy (CT) for acute myeloid leukemia (AML) we administered recombinant human granulocyte- macrophage colony-stimulating factor (GM-CSF) to patients over the age of 65 years with newly diagnosed AML and to patients with early or second relapse. CT was 9-day 6-thioguanine, ara-C, and daunorubicin (TAD9) in newly diagnosed AML and sequential high-dose ara-C and mitoxantrone (S-HAM) for relapse. In patients whose bone marrow was free from blasts a continuous intravenous infusion of GM-CSF 250 micrograms/m2/d started on day 4 after CT. Thirty-six patients entered the study and 30 of them did receive GM-CSF. For comparison, a historical control group of 56 patients was used. Complete remission rate was 50% (18 of 36) versus 32% in controls (P = .09), and early death rate was 14% versus 39% (P = .009). Treatment with GM-CSF was not associated with major adverse events. Two patients showed a marked leukemic regrowth that was completely reversible in one patient and appeared to be GM-CSF independent in the other patient. Remission duration does not seem to be reduced after GM-CSF. Under GM-CSF the blood neutrophils recovered 6 and 9 days earlier in the TAD9 (P = .009) and S-HAM (P = .043) groups associated with a rapid clearance of infections in most patients. We conclude that GM-CSF was of therapeutic benefit to our patients and this provides a basis for larger controlled trials.

scholarly journals Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony- stimulating factor

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1766-1769
Author(s):  
EH Estey ◽  
D Dixon ◽  
HM Kantarjian ◽  
MJ Keating ◽  
K McCredie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Early Death ◽  
Newly Diagnosed ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

scholarly journals Effect of recombinant granulocyte-macrophage colony-stimulating factor on murine thrombocytopoiesis in vitro and in vivo

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1433-1438
Author(s):  
T Ishibashi ◽  
H Kimura ◽  
Y Shikama ◽  
T Uchida ◽  
S Kariyone ◽  
...  
Keyword(s):  
Tritiated Thymidine ◽  
In Vivo Studies ◽  
Colony Stimulating Factor ◽  
Serum Free ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

To investigate the effect of recombinant granulocyte-macrophage colony- stimulating factor (rGM-CSF) on murine megakaryocytopoiesis in vitro, the factor was added to both serum-free colony assays and liquid marrow cultures. GM-CSF had a significant megakaryocytic colony-stimulating activity. After 2 hours of preincubation with and without 10 ng/mL rGM- CSF, the percentage of megakaryocyte colony-forming cell (CFU-MK) in DNA synthesis was determined by tritiated-thymidine suicide using colony growth. The reduction of CFU-MK colony numbers in marrow culture was 47.5% +/- 9.9%, 20.9% +/- 5.2% (control), respectively, indicating that the factor affected cell cycle at CFU-MK levels. When acetylcholinesterase (AchE) production was measured fluorometrically after 4 days of liquid culture, rGM-CSF elicited an increase in AchE activity in a dose-dependent fashion. To determine if the hematopoietin acts directly on megakaryocytic differentiation, 2 ng/mL rGM-CSF was added to serum-free cultures of 295 single megakaryocytes isolated from CFU-MK colonies. An increase in size was observed in 65% of cells initially 10 to 20 microns in diameter, 71% of cells 20 to 30 microns, and 40% of cells greater than 30 microns. Conversely, in absence of GM- CSF, 17%, 31%, and 10% of cells in each group increased in diameter. These data suggest that rGM-CSF promotes murine megakaryocytopoiesis in vitro and that the response to the factor is direct. To determine if the factor influences megakaryocytic/thrombocytic lineage in vivo, 1 and 5 micrograms of rGM-CSF were administered intraperitoneally every 12 hours for 6 consecutive days. Although a two- to three-fold increase in peripheral granulocytes was observed, neither megakaryocytic progenitor cells or platelets changed. Histologic analysis of bone marrow megakaryocytes showed no increase in size and number. The in vivo studies demonstrated no effect of GM-CSF on thrombocytopoiesis. The discrepancies between the in vitro and in vivo effects of GM-CSF require additional investigations.

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