scholarly journals Lack of effect of the human GM-CSF analog E21R on the survival of primary human acute myeloid leukemia cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3230-3232 ◽  
Author(s):  
Ira Jakupovic ◽  
Victoria L. Grandage ◽  
David C. Linch ◽  
Asim Khwaja
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cell Number ◽  
Gm Csf ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid Leukemia Cells ◽  
Macrophage Colony ◽  
Acute Myeloid

Abstract The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R binds to the GM-CSF receptor complex with low affinity and acts as a competitive antagonist. In addition, it has been reported to be a potent direct activator of apoptosis in primary human acute myeloid leukemia (AML) cells. We have confirmed the ability of E21R to neutralize the biologic effects of GM-CSF and investigated its activity on primary AML blasts. We find that it failed to induce cell death in blast cells from 23 separate AML cases treated in vitro at concentrations of E21R up to 30 μg/mL. Significant cell death resulted in all cases after incubation with cytosine arabinoside. The lack of effect of E21R on AML blasts was unlikely to be due to an absence of functional GM-CSF receptors because 13 cases demonstrated an increase in cell number with the addition of exogenous GM-CSF. These results do not support the use of E21R for the treatment of AML. (Blood. 2004;103: 3230-3232)

scholarly journals Treatment with interleukin-3 plus granulocyte-macrophage colony- stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2674-2679
Author(s):  
K Bhalla ◽  
C Holladay ◽  
Z Arlin ◽  
S Grant ◽  
AM Ibrado ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Combined Treatment ◽  
Hematopoietic Growth Factors ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Acute Myeloid

Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL- 3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.

scholarly journals Treatment with interleukin-3 plus granulocyte-macrophage colony- stimulating factors improves the selectivity of Ara-C in vitro against acute myeloid leukemia blasts

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2674-2679 ◽  
Author(s):  
K Bhalla ◽  
C Holladay ◽  
Z Arlin ◽  
S Grant ◽  
AM Ibrado ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mononuclear Cells ◽  
Combined Treatment ◽  
Hematopoietic Growth Factors ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony ◽  
Acute Myeloid

Abstract Hematopoietic growth factors (HGFs) interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) individually have been shown to increase the percentage of acute myeloid leukemia (AML) blasts in S phase and enhance the cytotoxic effects of Ara-C against these blasts in culture. We compared in vitro the effects of a combined treatment with GM-CSF (10 ng/mL) plus IL-3 (10 ng/mL) on the metabolism and cytotoxicity of Ara-C in normal bone marrow mononuclear cells (NBMMC) and AML blasts. NBMMC from six healthy volunteers and AML blasts from 10 patients were incubated for 20 hours with or without IL- 3 plus GM-CSF, followed by a concurrent treatment with Ara-C for 4 additional hours. Exposure to the HGFs and Ara-C produced significantly higher intracellular Ara-CTP levels as well as higher Ara-CTP/dCTP pool ratios in AML blasts as compared with NBMMC. Treatment with HGFs resulted in [3H] Ara-C DNA incorporation that was significantly higher in AML blasts versus NBMMC. This selective improvement of Ara-C metabolism in AML blasts was associated with an enhanced Ara-C-mediated leukemia colony-forming unit (CFU) growth inhibition. In contrast, exposure to HGFs resulted in an improved colony growth of normal CFU granulocyte-monocyte and CFU-granulocyte, erythroid, monocyte, megakaryocyte. These in vitro studies indicate that a combined treatment with IL-3 plus GM-CSF may improve the selectivity of Ara-C against AML blasts.

scholarly journals Conjugation of Lentivirus to Paramagnetic Particles via Nonviral Proteins Allows Efficient Concentration and Infection of Primary Acute Myeloid Leukemia Cells

2005 ◽  
Vol 79 (20) ◽  
pp. 13190-13194 ◽  
Author(s):  
Lucas Chan ◽  
Darren Nesbeth ◽  
Taylor MacKey ◽  
Joanna Galea-Lauri ◽  
Joop Gäken ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Virus ◽  
Surface Proteins ◽  
Virus Envelope ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

ABSTRACT Nonviral producer cell proteins incorporated into retroviral vector surfaces profoundly influence infectivity and in vivo half-life. We report the purification and concentration of lentiviral vectors using these surface proteins as an efficient gene transduction strategy. Biotinylation of these proteins and streptavidin paramagnetic particle concentration enhances titer 400- to 2,500-fold (to 109 CFU/ml for vesicular stomatitis virus G protein and 5 × 108 for amphotropic murine leukemia virus envelope). This method also uses newly introduced membrane proteins (B7.1 and ΔLNGFR) directed to lentiviral surfaces, allowing up to 17,000-fold concentrations. Particle conjugation of lentivirus allows facile manipulation in vitro, resulting in the transduction of 48 to 94% of human acute myeloid leukemia blasts.

MYC-induced human acute myeloid leukemia requires a continuing IL-3/GM-CSF costimulus

Blood ◽  
2020 ◽  
Vol 136 (24) ◽  
pp. 2764-2773
Author(s):  
Elizabeth Bulaeva ◽  
Davide Pellacani ◽  
Naoto Nakamichi ◽  
Colin A. Hammond ◽  
Philip A. Beer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Immunodeficient Mice ◽  
Gm Csf ◽  
Human Cd34 ◽  
Human Acute Myeloid Leukemia ◽  
Malignant State ◽  
Macrophage Colony ◽  
Acute Myeloid

Abstract Hematopoietic clones with leukemogenic mutations arise in healthy people as they age, but progression to acute myeloid leukemia (AML) is rare. Recent evidence suggests that the microenvironment may play an important role in modulating human AML population dynamics. To investigate this concept further, we examined the combined and separate effects of an oncogene (c-MYC) and exposure to interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) on the experimental genesis of a human AML in xenografted immunodeficient mice. Initial experiments showed that normal human CD34+ blood cells transduced with a lentiviral MYC vector and then transplanted into immunodeficient mice produced a hierarchically organized, rapidly fatal, and serially transplantable blast population, phenotypically and transcriptionally similar to human AML cells, but only in mice producing IL-3, GM-CSF, and SCF transgenically or in regular mice in which the cells were exposed to IL-3 or GM-CSF delivered using a cotransduction strategy. In their absence, the MYC+ human cells produced a normal repertoire of lymphoid and myeloid progeny in transplanted mice for many months, but, on transfer to secondary mice producing the human cytokines, the MYC+ cells rapidly generated AML. Indistinguishable diseases were also obtained efficiently from both primitive (CD34+CD38−) and late granulocyte-macrophage progenitor (GMP) cells. These findings underscore the critical role that these cytokines can play in activating a malignant state in normally differentiating human hematopoietic cells in which MYC expression has been deregulated. They also introduce a robust experimental model of human leukemogenesis to further elucidate key mechanisms involved and test strategies to suppress them.

scholarly journals Common binding structure for granulocyte macrophage colony-stimulating factor and interleukin-3 on human acute myeloid leukemia cells and monocytes

Blood ◽  
1990 ◽  
Vol 75 (7) ◽  
pp. 1439-1445 ◽  
Author(s):  
LM Budel ◽  
O Elbaz ◽  
H Hoogerbrugge ◽  
R Delwel ◽  
LA Mahmoud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
High Affinity ◽  
Human Acute Myeloid Leukemia ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) control the proliferation of human acute myeloid leukemia (AML) cells in vitro. Previously, we have shown that receptors for GM-CSF and IL-3 are often coexpressed on AML cells. Here we present experiments with purified AML blasts, normal monocytes, and granulocytes that were conducted to analyze the properties of GM-CSF and IL-3 binding proteins in more detail. On AML cells from eight cases we demonstrate two types of GM-CSF receptors: one with low affinity (dissociation constant [kd] 5.1 to 24.8 nmol/L) and one with a high affinity (kd 31 to 104 pmol/L). These AML cells also expressed high affinity receptors for IL-3 (kd 24 to 104 pmol/L). Cross-competition experiments showed that an excess concentration of nonlabeled IL-3 completely prevented the high affinity binding of radiolabled GM-CSF. This competition occurred at 37 degrees C as well as 4 degrees C. Low affinity GM-CSF binding was not affected by IL-3. Binding of radiolabeled IL-3 could be prevented by nonlabeled GM-CSF. In certain cases, this competition was complete, whereas in others only partial (49% to 77%) reduction of the radiolabeled IL-3 binding was seen. On the basis of these ligand binding features, we propose the existence of three receptor types on AML cells: (1) low affinity GM-CSF receptors that do not bind IL-3, (2) dual high affinity GM-CSF/IL-3 receptors, and (3) high affinity IL-3 receptors that do not bind GM-CSF. We could also demonstrate these receptor types on normal monocytes. In addition, a fourth type of receptor was apparent on normal granulocytes (4), incapable of binding IL-3 and with an intermediate affinity for GM-CSF (approximately 400 pmol/L). Chemical crosslinking showed that GM-CSF and IL-3 both bind to proteins with molecular weight values of 130, 105, and 75, which provides additional evidence for the existence of a common GM-CSF/IL-3 receptor complex.

scholarly journals AZD1152 Rapidly and Negatively Affects the Growth and Survival of Human Acute Myeloid Leukemia Cells In vitro and In vivo

2009 ◽  
Vol 69 (10) ◽  
pp. 4150-4158 ◽  
Author(s):  
Adedayo Oke ◽  
Daniel Pearce ◽  
Robert W. Wilkinson ◽  
Claire Crafter ◽  
Rajesh Odedra ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cells ◽  
Growth And Survival ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid
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