Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of a cell culture system for the in vitro cloning and clonal differentiation of normal hematopoietic cells made it possible to identify the proteins that regulate growth and differentiation of different hematopoietic cell lineages and the change in normal controls that produce leukemia. A model system with myeloid cells has identified different myeloid cell colony-inducing proteins, which we called MGI-1 (= CSF, including IL-3). There is another protein that we first described in 1976 and called MGI-2 in 1980 that induces differentiation of myeloid cells to macrophages or granulocytes without inducing the clonal growth of myeloid cells. The four CSF proteins and IL-1 induce the production of MGI-2 in myeloid cells and MGI-2 induces the production of GM-CSF. This shows the participation of MGI-2 in the network of interactions with different myeloid regulatory proteins. Using a monoclonal antibody to MGI-2, amino acid sequencing, and recombinant protein, we have shown in collaboration with the Genetics Institute that the major form of MGI-2 (MGI-2A) is IL-6. This shows that IL-6 is a myeloid cell differentiation inducing protein. The results also suggest new clinical potentials for MGI-2/IL-6.
 ...
PMID:The molecular regulators of macrophage and granulocyte development. Role of MGI-2/IL-6. 266 Jun 99

The conversion of normal haemopoietic stem cells to myelodysplastic and then to leukaemic cells is marked by a number of events leading to progressive genetic changes in the abnormal clonal population. Cytogenetic evidence points to abnormalities at specific chromosomal locations, commonly involving chromosomes 5 and 7, where there are a particular concentration of genes directly involved in the regulation of haemopoietic proliferation and differentiation. These include GM-CSF, IL-3, M-CSF, erythropoietin and others. Other genes that may be involved in the preleukaemic process are so-called 'oncogenes' such as met on chromosome 7q and fms on 5q (which codes for the M-CSF receptor) that may be deleted or translocated. The ras gene family is activated by point mutations in a wide variety of malignant states, including myelodysplasia and acute myeloblastic leukaemia. At the present time we do not know the cause of these genetic lesions, their functional significance or the sequence in which they occur.
 ...
PMID:Oncogenes in the myelodysplastic syndrome. 267 42

PGM-1 is a transplantable leukemia of C3H/HeJ mice growing as a population of undifferentiated blast cells with a predisposition to form subcutaneous tumors and to grow in lymphoid organs. Cell survival and proliferation in vitro are absolutely dependent on stimulation by hemopoietic growth factors, and up to 100% of tumor cells can form colonies of mature granulocytes and/or macrophages in semisolid cultures, the colonies containing no clonogenic cells. Most clonogenic cells in the leukemic population respond to stimulation by multi-colony-stimulating factor (IL-3) or GM-CSF, but some respond also to M-CSF, G-CSF, IL-4, IL-5, or IL-6. In their surface phenotype and proliferative characteristics in vitro, PGM-1 leukemic cells resemble normal granulocyte-macrophage progenitor cells, and the leukemia may be a useful model for human chronic myeloid leukemia.
Leukemia 1989 Nov
PMID:PGM-1: a transplantable murine leukemia of granulocyte-macrophage progenitor cells. 268 46

Different clones of myeloid leukemic cells can be induced to differentiate to mature macrophages and/or granulocytes by hematopoietic regulatory proteins and by other compounds. We now show that induction of differentiation in different clones of myeloid leukemic cells with the normal hematopoietic proteins granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), or interleukin 3 and by compounds such as dexamethasone or cytosine arabinoside (ara C) induces the expression of genes for the myeloid differentiation inducing protein MGI-2 that we have shown is interleukin 6 (IL-6) and for GM-CSF. We have previously shown that induction of differentiation with interleukin-1, IL-6, or bacterial lipopolysaccharide (LPS) also induces IL-6 and GM-CSF gene expression. Treatment of these leukemic clones with hematopoietic proteins that do not induce differentiation did not induce IL-6 or GM-CSF gene expression. The results indicate that induction of IL-6 and GM-CSF gene expression is part of the normal differentiation program in myeloid cells and support our previous evidence that there is transregulation of gene expression between different hematopoietic regulatory proteins.
Leukemia 1989 Dec
PMID:Regulation of the genes for interleukin-6 and granulocyte-macrophage colony stimulating factor by different inducers of differentiation in myeloid leukemic cells. 268 77

Injection of a single dose of recombinant human interleukin-1 alpha (r-hu-IL-1 alpha) into mice 24 hr after 5-fluorouracil (FU) treatment resulted in an increased rate of recovery of three types of colony-forming cells (CFCs) in the bone marrow. Myeloid progenitors with high proliferative potential (responsive to CSF-1 + IL-3 + IL-1 alpha), low proliferative potential (responsive to CSF-1), megakaryocyte progenitors, and total nucleated cells per femur increased up to 5-fold, 7-fold, 3-fold, and 3-fold, respectively, in a dose related fashion compared with the control FU treated marrows. The kinetics of FU kill and recovery of these CFCs are shown.
Leukemia 1989 Dec
PMID:In vivo effects of interleukin-1 alpha on regenerating mouse bone marrow myeloid colony-forming cells after treatment with 5-fluorouracil. 268 78

The chromosome alterations specifically associated with leukaemia are found largely in the regions where the genes for the haemopoietic growth factors (as well as other regulatory molecules or their receptors) are located, indicating a crucial role of the growth factors in leukaemogenesis. However, growth factor genes per se do not generally induce leukaemia when inserted into normal haemopoietic cells, although they will do so if they are inserted into immortalized haemopoietic stem cell lines. The response of AML cells to these growth factors is extremely heterogeneous, and the tilting of the balance between self-reproduction (leading to perpetuation of the leukaemic process) and differentiation ('death' of the malignant cells) depends on several parameters, on the type and combination of factors to which the cells are exposed, with IL-3 and GM-CSF tending to favour self-renewal, and G-CSF and M-CSF tending to favour differentiation. These findings open the possibility to consider the use of growth factors to control the leukaemic process, although such treatment should be approached with considerable caution, and on an individual patient basis.
 ...
PMID:Haemopoietic growth factors: their role in acute myeloblastic leukaemia. 268 18

It has been postulated that the disruption of the normal hormonal regulation of blood cell formation and proliferation leads to the autonomous growth of hematopoietic progenitors or stem cells and thus to leukeamia. We have utilized established hematopoietic cell lines to establish the different mechanism by which growth autonomy is acquired. The analysis of thirteen spontaneous factor-independent mutants revealed that the majority (12/13) secreted a factor that stimulated growth of the parental cell line. Thus, autocrine stimulation may be a important mechanism by which normal growth control is disrupted. This is supported by the observation of Young and Griffin (1987) that some cells isolated from patients with acute myeloblastic leukemia (AML) autogenously produce growth factor. In the majority of Dind mutants more closely examined, growth factor gene activation was due to the juxtapostion of a retrotransposon. Although the exact nature of the involvement of human retroviruses in inducing leukemia has not been elucidated, one could envisage that altered growth factor regulation due to integration of the virus may play an important role. The existence of a second class of Dind mutants that have obtained factor-independence by a mechanism not involving factor production concurs with the acquisition of factor-independent growth in hematopoietic cells after introduction of some oncogenes. Several models have been proposed to explain how oncogenes may "short circuit" and thus activate the normal signal transduction pathway by mimicking the active receptor, transducer, or effector (Weinberg, 1985). To investigate more closely the role of autocrine stimulation in the induction of growth autonomy and tumorigenicity, retroviral vectors expressing either GM-CSF or IL3 were introduced into factor-dependent hematopoitic cell lines. Non-linear clonability of infected cell lines in the absence of exogenous growth factor and inhibition of proliferation by antiserum supported a model of autocrine stimulation. However, a secondary event, correlated with amount of factor released, often occurred that abrogated the requirement for secreted CSF. Growth of cells in which this alteration had occured was cell-density independent and could not be blocked by antibody. It has been postulated that autogenous factor may react with its receptor intracellularly (Lang et al., 1985). The results presented here cannot exclude that the secondary events may allow the internal interaction of receptor and factor.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Conversion of factor-dependent myeloid cells to factor independence: autocrine stimulation is not coincident with tumorigenicity. 273 34

The proliferative and maturation abilities of bone marrow progenitors in patients with refractory anemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T) have previously been investigated in vitro using impure sources of colony stimulating activity. Here we report studies that were concerned with defining growth factor responses of RAEB progenitors (RAEB-CFU) in colony culture using pure hematopoietic growth factors. Marrow cells of 10 RAEB patients were cultured with recombinant IL3, GM-CSF, G-CSF, M-CSF and EPO. Factor dependent colony growth of four patients was examined in detail cytologically. The analysis revealed notable deficiencies in the colony forming spectrum as compared with normal marrow: although granulocytic colonies were formed in all of these four RAEB cases, macrophage colonies could not be induced in 1/4 cases and eosinophilic and erythroid colony formation could not be propagated in 2/4 cases with the proper stimuli. These findings are indicative of the intrinsic incapabilities of RAEB-CFU to mature along certain differentiation pathways in response to the growth factors. We then determined the surface phenotypes of RAEB-CFU using MoAbs Vim-2 (myelomonocytic) and B13C5 (CD34) following dual labeling and fluorescence activated cell sorting and subsequent culture of the separately sorted BI3C5+/Vim-2+, BIC5+/Vim-2-, BI3C5-/Vim-2+ and BIC5-/Vim-2- cells. In normal marrow most clonogenic cells were recovered from the BI3C5+/Vim-2- fraction. In contrast, in RAEB marrow increased proportions of the colony forming cells were BI3C5+/Vim-2+, BI3C5-/Vim-2+, or BI3C5-. The altered distribution of surface immunophenotypes of RAEB-CFU provides further evidence for the imbalance of maturation in the progenitor cell compartment. The results are discussed in view of the concept that the inabilities of the RAEB hematopoietic precursors to mature in response to the hematopoietic growth factors are partial and variable, but may culminate in a progressive loss of the differentiation competence of the progenitors when leukemia evolves.
 ...
PMID:Characterization of clonogenic cells in refractory anemia with excess of blasts (RAEB-CFU): response to recombinant hematopoietic growth factors and maturation phenotypes. 278 35

The c-fms proto-oncogene encodes the receptor for the mononuclear phagocyte colony stimulating factor, CSF-1. Although the tyrosine kinase activity of the CSF-1 receptor is stimulated by its ligand, the viral oncogene, v-fms, encodes a constitutive receptor kinase that can transform both fibroblasts and hematopoietic cells by a nonautocrine mechanism. Mutations in the c-fms gene as well as a critical alteration of the distal 3' coding sequences appear to be responsible for fully activating its latent transforming potential. The v-fms gene can convert CSF-1 or IL-3 dependent hematopoietic cell lines to factor independence and render them tumorigenic. Expression of the v-fms gene product does not transmodulate the normal receptors for CSF-1 or IL-3 and affects neither their affinity, number, nor potential to be independently down-regulated by their ligands or by phorbol esters. The ability of v-fms to transform hematopoietic target cells suggests that critical alterations in the c-fms proto-oncogene might similarly contribute to leukemia.
 ...
PMID:Fibroblast and hematopoietic cell transformation by the fms oncogene (CSF-1 receptor). 282 35

We have recently shown that Abelson murine leukemia (A-MuLV) virus can transform cells in large mixed colonies to give tumorigenic myeloid cell lines capable of autonomous growth in vitro. Initial studies revealed that granulocyte-macrophage colony-stimulating factor (GM-CSF) production was consistently activated in these cells. Using a sensitive S1 RNA mapping technique and additional bioassays, we have now obtained evidence of expression of other hemopoietic growth factor genes. Uniformly 32P-labeled, single-stranded DNA probes (greater than 4 x 10(8) cpm/micrograms) were generated for interleukin 3 (IL-3) and GM-CSF using pTZ based vectors. IL-3 mRNA was detected in four of four cloned transformants (from two different infections) at approximately 1% of the level seen in pokeweed mitogen (PWM)-stimulated spleen cells. GM-CSF mRNA was detected in the two clones that showed the highest IL-3 mRNA levels. Medium conditioned by these cells was able to stimulate IL-3-dependent 32D cells, and IL-3- and GM-CSF-dependent B6SUtA cells, and also supported the growth of a variety of single and multilineage colonies in assays of mouse marrow cells even in the presence of neutralizing antibodies to GM-CSF. Rearrangements of the IL-3 and GM-CSF genes were not apparent by Southern blot analysis. Additional bioassays revealed the presence of two other growth factors: IL-6 (hybridoma growth factor or Ifn-beta 2) assayed on B13.29 cells, a factor-dependent murine B-cell hybridoma; and a new pre-B-cell stimulatory factor different from any of the above. Elucidation of the mechanism underlying this phenomenon may provide important insights into the regulation of hemopoietic growth factor gene expression and the role such genes play in human leukemogenesis.
 ...
PMID:Activation of multiple hemopoietic growth factor genes in Abelson virus-transformed myeloid cells. 284 75


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