Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase

Blood ◽  
2003 ◽  
Vol 102 (10) ◽  
pp. 3786-3792 ◽  
Author(s):  
Frank El Ouriaghli ◽  
Elaine Sloand ◽  
Lori Mainwaring ◽  
Hiroshi Fujiwara ◽  
Keyvan Keyvanfar ◽  
...  
Keyword(s):  
Growth Factors ◽  
Chronic Myelogenous Leukemia ◽  
Neutrophil Elastase ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Colony Stimulating Factor ◽  
Growth Environment ◽  
Cd34 Cells ◽  
Stimulating Factor

AbstractClinical observations suggest that in chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph+) clone has a growth advantage over normal hematopoiesis. Patients with CML have high levels of neutrophil elastase, which has recently been shown to antagonize the action of granulocyte-colony-stimulating factor (G-CSF) and other growth factors. We therefore compared the effect of elastase on the growth of normal and CML progenitor cells. In 10-day suspension cultures of normal or CML CD34+ cells supplemented with G-CSF, stem cell factor (SCF), and granulocyte macrophage-colony-stimulating factor (GM-CSF), CML cells had diminished sensitivity to the growth inhibitory effect of elastase. When equal numbers of CML and normal CD34+ cells were cocultured for 10 days, there was no change in the relative proportions of normal and leukemic cells (measured by fluorescence in situ hybridization [FISH] or flow cytometry). However, when elastase was added, CML cells predominated at the end of the culture period (78% vs 22% with 1 μg/mL and 80% vs 20% with 5 μg/mL elastase). CML neutrophils substituted effectively for elastase in suppressing the proliferation of normal CD34+ cells, but this effect was abrogated by serine protease inhibitors. These results suggest that elastase overproduction by the leukemic clone can change the growth environment by digesting growth factors, thereby giving advantage to Ph+ hematopoiesis. (Blood. 2003; 102:3786-3792)

scholarly journals Production of Colony-stimulating Factor by Malignant Leukocytes

Blood ◽  
1974 ◽  
Vol 43 (5) ◽  
pp. 749-756 ◽  
Author(s):  
David W. Golde ◽  
Belina Rothman ◽  
Martin J. Cline
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Csf Production

Abstract There is considerable evidence supporting a role for colony-stimulating factor (CSF) as a humoral regulator of leukopoiesis. Data on CSF levels in the serum and urine of patients with leukemia and on the in vitro responsiveness of leukemic cells to CSF have suggested a basis for considering leukemia as a primary disorder of leukopoietic regulation. We examined the question of leukemic cell production of CSF. Conditioned medium from cultured leukemic cells was tested for colony-stimulating activity against normal human bone marrow using a two-layer agar colony assay technique. The cells from patients with acute myelogenous leukemia and a patient with chronic myelogenous leukemia in blast crisis did not elaborate CSF nor did acute lymphocytic leukemia cells. CSF production was documented with cells obtained from patients with chronic myelogenous leukemia in the chronic phase and two patients with acute myelomonocytic leukemia. In acute leukemia the cellular production of CSF correlated closely with morphologic and functional maturation along the monocyte-macrophage line. Evidence was obtained that the adherent cells within the leukemic population were primarily responsible for CSF production. We interpret these data to indicate that neoplastic hematopoietic cells may produce CSF in relation to their capacity for mononuclear leukocyte differentiation.

Identification of human chronic myelogenous leukemia progenitor cells with hemangioblastic characteristics

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2733-2740 ◽  
Author(s):  
Baijun Fang ◽  
Chunmei Zheng ◽  
Lianming Liao ◽  
Qin Han ◽  
Zhao Sun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Blood Cells ◽  
Fusion Gene ◽  
Fetal Liver ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Leukemic Cells

AbstractOverwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. Interestingly, the BCR/ABL fusion gene, which is present in chronic myelogenous leukemia (CML), was also detected in the endothelial cells of patients with CML, suggesting that CML might originate from hemangioblastic progenitor cells that can give rise to both blood cells and endothelial cells. Here we isolated fetal liver kinase-1–positive (Flk1+) cells carrying the BCR/ABL fusion gene from the bone marrow of 17 Philadelphia chromosome–positive (Ph+) patients with CML and found that these cells could differentiate into malignant blood cells and phenotypically defined endothelial cells at the single-cell level. These findings provide direct evidence for the first time that rearrangement of the BCR/ABL gene might happen at or even before the level of hemangioblastic progenitor cells, thus resulting in detection of the BCR/ABL fusion gene in both blood and endothelial cells.

scholarly journals Recombinant human granulocyte colony-stimulating factor repairs the abnormalities of neutrophils in patients with myelodysplastic syndromes and chronic myelogenous leukemia

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 404-411 ◽  
Author(s):  
A Yuo ◽  
S Kitagawa ◽  
T Okabe ◽  
A Urabe ◽  
Y Komatsu ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Myelodysplastic Syndromes ◽  
Neutrophil Function ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Vitro Effect ◽  
O2 Production ◽  
Stimulating Factor

We examined the in vitro effect of recombinant human granulocyte colony- stimulating factor (rhG-CSF) on neutrophil anomalies in 20 patients with myelodysplastic syndromes (MDS) and eight patients with chronic myelogenous leukemia (CML). Neutrophil alkaline phosphatase (NAP) activity was determined in nine MDS patients and eight CML patients by a scoring method. NAP scores were decreased in six of the nine patients with MDS and in all of the patients with CML. In all patients with these diseases, NAP scores increased by incubating the blood with rhG- CSF. An increase in NAP scores by rhG-CSF was observed even at a concentration of 1 U/mL in patients with MDS but was observed only at higher concentrations (1,000 to 10,000 U/mL) in patients with CML. Significant increases in NAP scores occurred at 12 hours' incubation in patients with MDS, whereas the increase was more gradual in patients with CML. This time course difference was thought to be due mainly to the difference in cell populations of circulating myeloid cells between MDS patients and CML patients. Induction of NAP activity by rhG-CSF in patients with both these diseases was suppressed by the addition of inhibitors of RNA or protein synthesis. Neutrophil superoxide anion (O2- ) production induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was determined in the other 11 patients with MDS. This neutrophil function was decreased in seven of the 11 patients with MDS, normal in two patients, and increased in two patients. Preincubation with rhG-CSF caused a significant increase in fMLP-induced O2- production in nine of the 11 patients with MDS. rhG-CSF enhanced this neutrophil function in a time- and dose-dependent manner, and maximal stimulation was observed at 2,000 to 4,000 U/mL of rhG-CSF and at five to ten minutes' incubation. The present results show that rhG-CSF is able to repair at least in part the neutrophil anomalies in these patients, and our data, especially for patients with MDS, suggest the clinical usefulness of rhG-CSF for this preleukemic disorder.

Bcr-Abl Efficiently Induces a Myeloproliferative Disease and Production of Excess Interleukin-3 and Granulocyte-Macrophage Colony-Stimulating Factor in Mice: A Novel Model for Chronic Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3829-3840 ◽  
Author(s):  
Xiaowu Zhang ◽  
Ruibao Ren
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Molecular Mechanisms ◽  
Myelogenous Leukemia ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The bcr-abl oncogene plays a critical role in causing chronic myelogenous leukemia (CML). Effective laboratory animal models of CML are needed to study the molecular mechanisms by which thebcr-abl oncogene acts in the disease progression of CML. We used a murine stem cell retroviral vector (MSCV) to transduce thebcr-abl/p210 oncogene into mouse bone marrow cells and found that expression of Bcr-Abl/p210 induced a myeloproliferative disorder that resembled the chronic phase of human CML in 100% of bone marrow transplanted mice in about 3 weeks. This CML-like disease was readily transplanted to secondary recipient mice. Multiple clones of infected cells were expanded in the primary recipients, but the leukemia was primarily monoclonal in the secondary recipient mice. Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Interestingly, we found that the leukemic cells expressed excess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the diseased mice. These studies demonstrate that expression of Bcr-Abl can induce a CML-like leukemia in mice much more efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cell(s). Our first use of this model for analysis of the molecular mechanisms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML.

Bcr-Abl Efficiently Induces a Myeloproliferative Disease and Production of Excess Interleukin-3 and Granulocyte-Macrophage Colony-Stimulating Factor in Mice: A Novel Model for Chronic Myelogenous Leukemia

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3829-3840 ◽  
Author(s):  
Xiaowu Zhang ◽  
Ruibao Ren
Keyword(s):  
Bone Marrow ◽  
Chronic Myelogenous Leukemia ◽  
Molecular Mechanisms ◽  
Myelogenous Leukemia ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

The bcr-abl oncogene plays a critical role in causing chronic myelogenous leukemia (CML). Effective laboratory animal models of CML are needed to study the molecular mechanisms by which thebcr-abl oncogene acts in the disease progression of CML. We used a murine stem cell retroviral vector (MSCV) to transduce thebcr-abl/p210 oncogene into mouse bone marrow cells and found that expression of Bcr-Abl/p210 induced a myeloproliferative disorder that resembled the chronic phase of human CML in 100% of bone marrow transplanted mice in about 3 weeks. This CML-like disease was readily transplanted to secondary recipient mice. Multiple clones of infected cells were expanded in the primary recipients, but the leukemia was primarily monoclonal in the secondary recipient mice. Mutation analysis demonstrated that the protein tyrosine kinase activity of Bcr-Abl/p210 was essential for its leukemogenic potential in vivo. Interestingly, we found that the leukemic cells expressed excess interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the diseased mice. These studies demonstrate that expression of Bcr-Abl can induce a CML-like leukemia in mice much more efficiently and reproducibly than in previously reported mouse CML models, probably due to efficient expression in the correct target cell(s). Our first use of this model for analysis of the molecular mechanisms involved in CML raises the possibility that excess expression of hematopoietic growth factors such as IL-3 and GM-CSF may contribute to the clinical phenotype of CML.

scholarly journals Expression of leukocyte alkaline phosphatase gene in normal and leukemic cells: regulation of the transcript by granulocyte colony- stimulating factor

Blood ◽  
1990 ◽  
Vol 76 (12) ◽  
pp. 2565-2571 ◽  
Author(s):  
A Rambaldi ◽  
M Terao ◽  
S Bettoni ◽  
ML Tini ◽  
R Bassan ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Polymorphonuclear Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Leukocyte Alkaline Phosphatase ◽  
Stimulating Factor

Abstract The levels of leukocyte alkaline phosphatase (LAP) messenger RNA (mRNA) are evaluated in B and T lymphocytes, monocytes, and polymorphonuclear cells (PMNs), and this transcript is found to be present only in PMNs. Precursors of the myelomonocytic pathway, represented by leukemic cells isolated from several cases of chronic myelogenous leukemia (CML) in its stable and blastic phase and acute myelogenous leukemia (AML), are devoid of LAP transcript. These data support the notion that LAP is a marker of the granulocyte terminal differentiation. Despite the absence of LAP mRNA in both the myeloid and the lymphoid precursors, nuclear run-on experiments show constitutive transcription of the LAP gene in leukemic cells obtained from AML, CML, as well as acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia (B-CLL). In CML and in chronic myelo-monocytic leukemia (CMML) PMNs, granulocyte colony- stimulating factor (G-CSF) specifically accumulates LAP mRNA without showing a substantial increase in the rate of transcription of the LAP gene. Once increased by G-CSF, LAP mRNA is very stable, showing a half- life of more than 4 hours in the presence of actinomycin-D. G-CSF is suggested to play a pivotal role in the modulation of LAP transcript in PMNs.

scholarly journals Recombinant human granulocyte colony-stimulating factor repairs the abnormalities of neutrophils in patients with myelodysplastic syndromes and chronic myelogenous leukemia

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 404-411 ◽  
Author(s):  
A Yuo ◽  
S Kitagawa ◽  
T Okabe ◽  
A Urabe ◽  
Y Komatsu ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Myelodysplastic Syndromes ◽  
Neutrophil Function ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Vitro Effect ◽  
O2 Production ◽  
Stimulating Factor

Abstract We examined the in vitro effect of recombinant human granulocyte colony- stimulating factor (rhG-CSF) on neutrophil anomalies in 20 patients with myelodysplastic syndromes (MDS) and eight patients with chronic myelogenous leukemia (CML). Neutrophil alkaline phosphatase (NAP) activity was determined in nine MDS patients and eight CML patients by a scoring method. NAP scores were decreased in six of the nine patients with MDS and in all of the patients with CML. In all patients with these diseases, NAP scores increased by incubating the blood with rhG- CSF. An increase in NAP scores by rhG-CSF was observed even at a concentration of 1 U/mL in patients with MDS but was observed only at higher concentrations (1,000 to 10,000 U/mL) in patients with CML. Significant increases in NAP scores occurred at 12 hours' incubation in patients with MDS, whereas the increase was more gradual in patients with CML. This time course difference was thought to be due mainly to the difference in cell populations of circulating myeloid cells between MDS patients and CML patients. Induction of NAP activity by rhG-CSF in patients with both these diseases was suppressed by the addition of inhibitors of RNA or protein synthesis. Neutrophil superoxide anion (O2- ) production induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was determined in the other 11 patients with MDS. This neutrophil function was decreased in seven of the 11 patients with MDS, normal in two patients, and increased in two patients. Preincubation with rhG-CSF caused a significant increase in fMLP-induced O2- production in nine of the 11 patients with MDS. rhG-CSF enhanced this neutrophil function in a time- and dose-dependent manner, and maximal stimulation was observed at 2,000 to 4,000 U/mL of rhG-CSF and at five to ten minutes' incubation. The present results show that rhG-CSF is able to repair at least in part the neutrophil anomalies in these patients, and our data, especially for patients with MDS, suggest the clinical usefulness of rhG-CSF for this preleukemic disorder.

Differential Regulation of Pro- and Anti-Apoptotic Genes by Bcr-Abl in an In Vitro Experimental Model of Chronic Myelogenous Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4244-4244
Author(s):  
Axel Gustavo Ulbrich ◽  
Ana Elisa B. Bueno-da-Silva ◽  
Gustavo P. Amarante-Mendes
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Activity ◽  
Philadelphia Chromosome ◽  
Specific Inhibitor ◽  
Differential Regulation ◽  
Myelogenous Leukemia ◽  
Leukemic Cells ◽  
Regulation Mechanism ◽  
Efficient Treatment

Abstract Leukemic cells from patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) are very resistant to apoptosis induced by DNA-damaging agents and other chemotherapeutic drugs, due to the presence of Bcr-Abl, a chimeric cytoplasmic tyrosine-kinase that confers both malignancy and resistance to apoptosis. Efficient treatment of CML can be achieved with a normal bone marrow transplant, which induces a graft-versus-leukemia response, and more recently by the use of the specific inhibitor imatinib mesylate (glivec. Novartis). Glivec blocks Bcr-Abl kinase activity and, as a consequence, the malignant cell dies by apoptosis. However most glivec-treated patients, mainly in the acute and blast phases, develop resistant forms of the disease. Since resistance to apoptosis in Bcr-Abl+ cells is probably related to the inhibition of mitochondrial release of cytochrome c, an obligatory step in most apoptotic pathways, we sought to investigate expression of Bcl-2 family genes in Bcr-Abl+, glivec-treated cells. By semi-quantitative RT-PCR we analyzed the gene expression of several pro- and anti-apoptotic molecules in the transduced cell line HL-60.Bcr-Abl and the wild-type HL-60, after a 1, 4 and 8h treatment with 10μM glivec. Bcr-Abl′s kinase activity is promptly inhibited by glivec (within 5 to 15min) and HL-60.Bcr-Abl cells begin to show mitochondrial depolarization 24h after treatment with the drug, dying 48h later, whereas no effects are observed in HL-60. Soon after glivec addition some genes are transcriptionally regulated in HL-60.Bcr-Abl cells. The major differences were observed for bcl-xL (2-fold reduction), c-flip (2-fold increase), bcl-w (30% increase) and mcl-1 (20% reduction). Some pro-apoptotic molecules such as noxa also displayed differential regulation in HL-60.Bcr-Abl cells. No differences were observed in HL-60 cells. In conclusion we describe a complex transcriptional regulation mechanism dependent on Bcr-Abl tyrosine-kinase activity, which has not been previously described by the use of microarrays, and could contribute to the understanding of the mechanisms involved in protection of apoptosis and drug resistance of Bcr-Abl+ cells.

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