Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human recombinant GM-CSF (rGM-CSF) is under investigation as a growth-protective agent for normal hematopoietic elements in phase I trials of myelosuppressive chemotherapy and in bone marrow transplantation. We determined the effect of rGM-CSF on the metabolism of high dose Ara-C in bone marrow mononuclear cells (BMMCs) from healthy volunteers and patients with ANLL. Cells were incubated with rGM-CSF alone, Ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF alone yielded approximately a twofold increment in intracellular dCTP pools in normal BMMCs but not in leukemic blasts. Exposure to rGM-CSF in conjunction with Ara-C corrected Ara-C-mediated declines in dCTP levels and decreased cytosine arabinoside triphosphate (Ara-CTP) accumulation in normal BMMCs but not in their leukemic counterparts. Furthermore, when exposure to Ara-C was preceded by treatment with rGM-CSF for 18 hr, an even greater reduction in the Ara-CTP/dCTP pool ratio was observed in normal versus leukemic elements; however, this did not significantly change Ara-C DNA incorporation in the two cell types. The differential effect of rGM-CSF on the phosphorylation of Ara-C in normal BMMCs versus leukemic blasts has potential implications for the use of a regimen consisting of rGM-CSF and high dose Ara-C in the treatment of ANLL with chemotherapy or autologous bone marrow transplantation.
 ...
PMID:Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. 326 63

Blast cell populations of forty nine individuals with acute myeloblastic leukemia (AML) were investigated for constitutive expression of genes for various hematopoietic growth factors. Fifteen samples constitutively exhibited messenger (m) RNA for colony stimulating factor for granulocytes (G-CSF). Eleven AML specimens produced mRNA specific for CSF for granulocyte and macrophages (GM-CSF). When probed for CSF for macrophages (M-CSF or CSF-1) specific hybridization signals became detectable in six samples. Five out of six blast cell populations transcribing M-CSF, synthesized G-, and GM-CSF mRNA's simultaneously, whereas another five leukemias transcribed G-, and GM-CSF genes exclusively. Furthermore, when specific bioassays were performed to detect secretion of biologically active CSF proteins by these leukemic blast samples, twelve out of fifteen G-CSF mRNA producing cell populations, eight out of eleven GM-CSF mRNA producing cell populations and one out of six M-CSF mRNA synthesizing samples, demonstrated release of the respective, functionally active CSF's into their culture supernatants. Our results show that gene transcription and protein secretion of hematopoietic growth factors are features that are frequently detected in leukemic myeloid blast cells and involve G-, GM-, and M-CSF. With respect to recent findings of receptiveness of leukemic colony forming cells (L-CFC) for proliferative stimuli provided by various hematopoietic growth factors, our findings point out a potential role of autocrineously produced CSF's in the pathophysiology of autonomous proliferation in AML.
 ...
PMID:Constitutive expression of hematopoietic growth factor genes by acute myeloblastic leukemia cells. 326 64

Cells of the factor-dependent hemopoietic cell line FDC-P1 become leukemic when injected intravenously to irradiated syngeneic mice. An analysis of 117 cell lines derived from 17 such leukemic mice showed that they displayed different patterns of growth in vitro ranging from full autonomy to absolute dependency on stimulation by granulocyte-macrophage colony stimulating factor (GM-CSF) or multipotential colony stimulating factor (multi-CSF). In contrast to parental FDC-P1 cells, even the factor-dependent variant cell lines were tumorigenic in vivo. The behavior of these latter cell lines could not be explained by hyperresponsiveness to CSFs or prolonged survival in the absence of CSFs. Conditioned media and cell lysates from leukemic cell lines from 8 animals contained variable levels of GM-CSF or multi-CSF. Proliferation of a GM-CSF-producing cell line was inhibited by anti-GM-CSF antibody, while both the parental FDC-P1 line and a leukemic line secreting multi-CSF remained unaffected. The patterns of growth in vitro of the leukemic cells tended to correlate with the amounts of CSFs produced. The observations show that leukemic transformation of FDC-P1 cells in vivo is frequently linked to autogenous production of hemopoietic growth factors. The range of abnormal in vitro growth patterns observed includes those typical of human acute myeloid leukemia, and the in vivo transformation model may be useful in analyzing the mechanisms leading to the development of this human disease.
 ...
PMID:In vitro growth patterns and autocrine production of hemopoietic colony stimulating factors: analysis of leukemic populations arising in irradiated mice from cells of an injected factor-dependent continuous cell line. 328 21

We studied the effects of recombinant human macrophage colony-stimulating factor (M-CSF) on the leukemic blast progenitors from 10 acute myeloblastic leukemia patients. Recombinant human (rh)M-CSF stimulated leukemic blast progenitors in methylcellulose in four patients, but the colonies by rhM-CSF were smaller in size and number than those by rh-granulocyte-CSF or human bladder carcinoma cell line 5637 conditioned medium. rhM-CSF did not increase the number of clonogenic cells in long-term suspension culture. The blast colony formation in methylcellulose and the exponential growth of clonogenic cells in long-term suspension culture are considered to reflect the terminal divisions and the self-renewal of blast progenitors, respectively. The results show that M-CSF stimulates terminal divisions weakly but does not stimulate self-renewal of leukemic blast progenitors. M-CSF did not induce differentiation of blasts either in methylcellulose or in suspension culture.
 ...
PMID:Effect of recombinant human M-CSF on the proliferation of leukemic blast progenitors in AML patients. 328 22

Many questions about the biology of AML remain to be answered. The initial genetic lesions that inhibit differentiation and increase the likelihood of self renewal have yet to be identified. Given the heterogeneity of this neoplasm, it is possible that many different mutational events may be capable of triggering leukemia. Alternatively, there may be only a small number of possible initial leukemic mutations, and the heterogeneous phenotype of the disease is determined by the evolution of different subclones that have acquired different secondary mutations. Studies with retroviral oncogenes have suggested that a common secondary event in an evolving myeloid tumor is the development of growth factor independence by either leukemic cell production of CSF or possibly constitutive activation of a CSF receptor. These mechanisms have not yet been established as important in human AML, although there is intriguing evidence to suggest that CSF genes are inappropriately activated in many cases.
 ...
PMID:The biology of acute myeloblastic leukemia. 332 41

In an agar-liquid double-layer colony assay in which myeloid leukemia colony-forming cells require the presence of both the lectin PHA and CSF for in vitro proliferation, colony formation of bone marrow cells derived from patients with a myelodysplastic syndrome (MDS) was studied. In five of 14 MDS and all five leukemic transformed MDS cases, colony formation was found to require both PHA and CSF. Three of these five PHA-dependent MDS cases progressed to overt leukemia within 1 year, one progressed from RA to RAEB, and one patient received AML chemotherapy. PHA-dependent colony formation was associated with higher bone marrow blast counts, but not directly to FAB type or cytogenetic abnormalities. In nine other MDS cases only CSF was required for colony formation. In these PHA-independent cases the course of the disease was stable during the observation time (5-17 months). Two types of colonies were observed in this in vitro system: colonies adherent and colonies nonadherent to the agar underlayer. The former consisted of terminally differentiated myeloid cells, and the latter comprised immature cells. This suggests that the percentage of adherent colonies formed in vitro may be used as a measure for the maturation defect in MDS. However, no correlation was found between the percentage of adherent colonies and progression to leukemia of the MDS cases. Our findings suggest that the dependency on PHA for in vitro colony formation of colony-forming cells in MDS is predictive for the progression to leukemia. However, the in vitro differentiation capacity has no apparent prognostic significance.
 ...
PMID:In myelodysplastic syndromes progression to leukemia is directly related to PHA dependency for colony formation and independent of in vitro maturation capacity. 339 24

A 47-year-old female with acute myeloid leukemia received HIV positive platelets during induction chemotherapy. 18 days later, coincident with the recovery of the bone marrow function, she developed an erythematous rash, mild lymphadenopathy, and nausea which disappeared within 10 days. A week later mild CSF pleocytosis consisting of mature lymphocytes and macrophages together with elevated CSF protein levels (1,080 mg/l) were observed suggesting mild aseptic meningitis, and the HIV was concomitantly isolated from CSF. The CSF abnormalities have improved and the patient is well and in remission after 3 cycles of chemotherapy. This case expands the clinical spectrum of HIV infection to include a primary syndrome during immunosuppression from an unrelated cause.
 ...
PMID:Primary infection with HIV in a severely immunosuppressed patient with acute leukemia. 347 78

Proliferation of acute myeloblastic leukemia (AML) cells in vitro is limited in most cases to a small subset of blasts that have several properties of stem cells. These leukemic colony-forming cells (AML-CFU) generally require addition of exogenous growth factors for proliferation in agar or methylcellulose. These factors can be supplied by media conditioned by phytohemagglutinin-stimulated normal leukocytes or by CSF-secreting tumor cell lines. However, the exact factor or factors required for stimulation of AML-CFU growth have not been defined. We compared the AML-CFU stimulatory activity of a human recombinant GM-CSF with that of GCT-CM, Mo-CM, and the PHA-leukocyte feeder system in 15 cases of AML. In each of the 12 cases that required exogenous growth factors for maximum AML-CFU growth, recombinant GM-CSF could replace either GM-CSF or Mo-CM, and could partially replace the PHA-leukocyte feeder system. These results indicate that this GM-CSF is a growth promoter of AML-CFU in these culture systems.
 ...
PMID:Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia. 348 12

Expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene was studied by Northern blot analysis in normal human hematopoietic cells and a series of leukemias. GM-CSF messenger (m)RNA was detected in activated T cells, but not in normal bone marrow cells, monocytes, or nonactivated T cells. In contrast, leukemic cells from 11 of 22 cases of acute myeloblastic leukemia expressed GM-CSF transcripts. Biologically active CSF was detected in supernatant conditioned by 6 of these 11 leukemias. Expression of the GM-CSF gene was not detected in "common" (pre-B cell) acute lymphoblastic leukemia (11 cases tested) or chronic myeloid leukemia (4 cases tested). These results show that the GM-CSF gene is constitutively expressed in a subset of patients with AML, and further suggest that expression of this gene could contribute to the abnormal growth properties characteristic of AML.
 ...
PMID:Constitutive expression of the granulocyte-macrophage colony-stimulating factor gene in acute myeloblastic leukemia. 349 36

A small subset of leukemic cells from most patients with acute myeloblastic leukemia (AML) have properties of stem cells and can be assayed by colony formation in agar or methylcellulose. Colony formation generally requires the addition of exogenous growth factors, but the exact factors required are incompletely defined. The AML colony-promoting activities of two recombinant human colony-stimulating factors (GM-CSF and G-CSF) were investigated by using blasts from 48 patients with AML. In nine cases, no colonies formed with either CSF. In seven cases colonies formed only in response to G-CSF and in 11 cases only in response to GM-CSF. In 21 cases colonies formed in response to either GM-CSF or G-CSF, and in 12 of these cases there was an additive effect between the two CSFs in determining maximum colony size. For cases responding to both GM- and G-CSF, the total number of colonies formed in response to the combination of both CSFs was almost always less than additive compared with the number of colonies formed in response to the individual CSFs. Further, the AML-CFU responding to either GM-CSF or G-CSF could not be distinguished by surface markers or by the cytochemical staining pattern of the colonies. These results suggest that there is considerable overlap between the GM-CSF- and G-CSF-responsive AML-CFU subpopulations in most cases. For five of seven cases, the combination of GM-CSF and G-CSF could replace a leukocyte feeder layer in providing maximum growth stimulation. These results indicate that GM-CSF and G-CSF are active growth factors for AML cells and are frequently additive in promoting maximum colony size.
 ...
PMID:The effects of GM-CSF and G-CSF in promoting growth of clonogenic cells in acute myeloblastic leukemia. 349 5


<< Previous 1 2 3 4 5 6 7 8 9 10