Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DCs) are believed to be the most potent antigen-presenting cells and may be important in the induction of anti-leukemia specific T cell responses. In this preliminary clinical study, a patient with chronic phase chronic myelogenous leukemia (CML) was vaccinated with autologous leukemic DCs following autologous peripheral blood stem cell transplantation (PBSCT). In an in vitro study, leukemic DCs were generated using granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha, and interleukin-4 from granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC fraction of this patient, and were found to be Ph1+, and to possess the morphologic and phenotypic characteristics of mature DCs. These cells could also elicit antigen specific immune responses, including a vigorous cytotoxicity specific to CML cells. In the clinical experiment, we obtained evidence that infused leukemic DCs could induce T cell clones expressing the same T cell receptor usage as a cytotoxic T cell line, suggesting that the immune repertoire includes tumor-reactive T cells. These cytotoxic T lymphocytes are activated in vivo. The vaccination of leukemic DC caused a decrease in the number of Ph1+ cells in the peripheral blood and bone marrow. These results indicate that the activity is an immunologically mediated phenomenon and vaccination therapy with leukemic DC following autologous PBSCT may be effective in treating CML.
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PMID:Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic dendritic cells following autologous peripheral blood stem cell transplantation. 1059 41

Primitive hematopoietic progenitors from some patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) express aberrant transcripts for interleukin 3 (IL-3) and granulocyte colony-stimulating factor (G-CSF), and exhibit autonomous proliferation in serum-free cultures that is inhibited by anti-IL-3 and anti-IL-3 receptor antibodies. Expression of the product of the Ph chromosome, the BCR/ABL oncogene, in mice by retroviral bone marrow transduction and transplantation induces CML-like leukemia, and some leukemic mice have increased circulating IL-3, and perhaps granulocyte-macrophage colony-stimulating factor (GM-CSF). These observations raise the possibility of autocrine or paracrine cytokine production in the pathogenesis of human CML. Mice with homozygous inactivation of the Il-3 gene, the Gm-csf gene, or both, were used to test the requirement for these cytokines for induction of CML-like disease by BCR/ABL. Neither IL-3 nor GM-CSF was required in donor, recipient, or both for induction of CML-like leukemia by p210 BCR/ABL. Use of novel mice deficient in both IL-3 and GM-CSF demonstrated that the lack of effect on leukemogenesis was not due to redundancy between these hematopoietic growth factors. Analysis of cytokine levels in leukemic mice where either donor or recipient was Il-3(-/-) indicated that the increased IL-3 originated from the recipient, suggestive of a host reaction to the disease. These results demonstrate that IL-3 and GM-CSF are not required for BCR/ABL-induced CML-like leukemia in mice and suggest that autocrine production of IL-3 does not play a role in established chronic phase CML in humans.
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PMID:Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL. 1122 92

In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.
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PMID:Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors. 2013 May 98