Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine derived from activated T cells, endothelial cells, fibroblasts, and macrophages. It stimulates myeloid and erythroid progenitors to form colonies in semisolid medium in vitro, as well as enhancing multiple differentiated functions of mature neutrophils, macrophages, and eosinophils. We have examined the binding of human GM-CSF to a variety of responsive human cells and cell lines. The most mature myelomonocytic cells, specifically human neutrophils, macrophages, and eosinophils, express the highest numbers of a single class of high affinity receptors (Kd approximately 37 pM, 293-1000 sites/cell). HL-60 and KG-1 cells exhibit an increase in specific binding at high concentrations of GM-CSF; computer analysis of the data is nonetheless consistent with a single class of high affinity binding sites with a Kd approximately 43 pM and 20-450 sites/cell. Dimethyl sulfoxide induces a 3-10-fold increase in high affinity receptors expressed in HL-60 cells, coincident with terminal neutrophilic differentiation. Finally, binding of 125I-GM-CSF to fresh peripheral blood cells from six patients with chronic myelogenous leukemia was analyzed. In three of six cases, binding was similar to the nonsaturable binding observed with HL-60 and KG-1 cells. GM-CSF binding was low, or in some cases, undetectable on myeloblasts obtained from eight patients with acute myelogenous leukemia. The observed affinities of the receptor for GM-CSF are consistent with all known biological activities. Affinity labeling of both normal neutrophils and dimethyl sulfoxide-induced HL-60 cells with unglycosylated 125I-GM-CSF yielded a band of 98 kDa, implying a molecular weight of approximately 84,000 for the human GM-CSF receptor.
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PMID:Characterization of the human granulocyte-macrophage colony-stimulating factor receptor. 282 52

Leukemic cells from a patient with chronic myelocytic leukemia (CML) basophilic crisis were examined in an in vitro clonogenic assay using recombinant human hematopoietic growth factors to elucidate the proliferative and differentiative behaviors. More than 90% of the leukemic cells showed the morphologic characteristics of basophils and were positive for CD11b and CD13. The phenotype of the leukemic cells was different from that of mast cells. In the clonogenic assay using various recombinant growth factors, the leukemic cells were responsive to interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF), but not to granulocyte-CSF (G-CSF), erythropoietin (Epo), or IL-4. IL-5 showed synergistic effects on colony formations induced by both IL-3 and GM-CSF. Transcripts of the GM-CSF receptor alpha chain gene were detected in the leukemic cells, but transcripts of the IL-4 receptor gene were not. Furthermore, c-kit and IL-7 receptor genes were expressed in the leukemic cells. Our results suggest that the differentiation pathway of basophils is different from that of mast cells, even though the receptor gene for stem cell factor (c-kit) was expressed on the basophilic leukemic cells, as it was on mast cells.
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PMID:Cellular characteristics of chronic myelocytic leukemia basophilic crisis cells: phenotype, responsiveness to and receptor gene expression for various kinds of growth factors and cytokines. 767 84

Normal expression of the hematopoietic growth factor receptor FLT3 (STK-1@Flk2) is limited to CD34+ stem/progenitor cells. We have evaluated the expression of FLT3 by RNase protection assay and Western blotting in 161 primary bone marrow (BM) samples from patients with leukemia. FLT3 RNA was found to be expressed at a higher level than in normal BM controls in 33 of 33 B-lineage acute leukemias, 11 of 12 acute myeloid leukemias (AMLs), and 3 of 11 T-cell acute leukemias (T-ALLs). Expression of FLT3 RNA was also observed in some cases of blast crisis CML. The FLT3 signal resulted from expression on the leukemic blasts, and was not caused by increased FLT3 expression on normal CD34+ stem/progenitor cells in the leukemic samples. To determine if FLT3 protein was also overexpressed, proteins were extracted from leukemic BM samples and screened by Western blotting with anti-FLT3 antisera. FLT3 protein was not detected in normal BM controls, but was found in 14 of 14 B-lineage ALLs, 36 of 41 AMLs, and 1 of 4 T-ALLs. Stimulation of patient samples with FLT3 ligand resulted in autophosphorylation of the FLT3 receptor, suggesting the receptor is functional in these cells. These data show that FLT3 RNA and protein are aberrantly expressed by AML and ALL cells in that CD34 expression and FLT3 expression are no longer synchronous, and suggest the possibility that overexpression of FLT3 could play a role in the survival and/or proliferation of malignant clones in acute myeloid and lymphoid leukemias.
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PMID:Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. 856 34

The 22nd chromosome is known mainly due to chromosome (Philadelphia) which is its derivative-a typical cytogenetic sign of chronic myeloid leukaemia (CML). The molecular genetic finding in these patients is the fused gene which developed by combination of the 3' part of the oncogene ABL from chromosome 9 and 5' part of the gene which developed by combination of the 3' part of the oncogene ABL from chromosome 9 and 5' part of the BCR "gene". The product of the gene retains the original kinase activity (ABL) which is even higher. Detection of BCR/ABL is an important diagnostic aid whic makes it possible to investigate residual diseases in patients after intensive treatment and transplantation of bone marrow and early detection of possible relapses. Among locuses of the 22nd chromosome the author mentions also the locus of the second one of the light immunoglobulin chains-lambda, incl. some of its "related" genes, the group of crystalline locuses (CRYB), the locus of the beta-chain of the GM-CSF receptor, the myoglobin locus (MB) and finally locus NF2 of central neurofibromatosis-bilateral neurinoma of the acoustic nerve.
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PMID:[The human genome--chromosome 22]. 859 11

Two novel cell lines (JURL-MK1 and JURL-MK2) have been established from the peripheral blood of a patient in the blastic phase of chronic myelogenous leukemia. The cells grow in a single cell suspension with doubling times of 48 h (JURL-MK1) and 72 h (JURL-MK2). Cytogenetic analysis has shown that JURL-MK1 is hypodiploid whereas JURL-MK2 is near triploid and that both cell lines retain t(9;22). Moreover, JURL-MK1 and JURL-MK2 have a bcr/abl-fused gene with the same junction found in the patient's fresh cells, and both cell lines express the b3/a2 type of hybrid bcr/abl mRNA. The morphology and immunophenotype of these cell lines are reminiscent of megakaryoblasts. In both lines, a limited but consistent percentage of cells expresses gpIIbIIIa (CD41a), gpIIIa (CD61) and CD36, with no expression of gplb (CD42b), glycophorin A, hemoglobin and CD34. Both cell lines are clearly positive for CD33, CD43, CD45RO and CD63, while CD13, CD44, CD54, CD30 and CD40 are specific features of JURL-MK2. Among cytokine receptors, CD117/SCF-R is strongly displayed by a large fraction of JURL-MK1 cells but is hardly detectable on about 20% JURL-MK2 cells. Both cell lines are clearly positive for CD25/IL2R alpha, while a marked expression of CD116/GM-CSF-R and CDw123/IL3R alpha is restricted to JURL-MK2. Induction of cell differentiation in vitro has demonstrated that TPA is able to modulate the JURL-MK1 phenotype, causing an increased expression of platelet-associated antigens. The JURL-MK2 phenotype is easily modulated by both TPA and DMSO, which cause an increased expression of CD41a and CD117 accompanied by a decreased expression of CD30. Proliferation studies demonstrated that JURL-MK1 cell growth is enhanced by stem cell factor, while JURL-MK2 proliferation is unaffected by this cytokine. JURL-MK1 and JURL-MK2 are two novel cell lines with divergent biological features, representing a 'two-sided' model for investigating new aspects of megakaryocytopoiesis.
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PMID:JURL-MK1 (c-kit(high)/CD30-/CD40-) and JURL-MK2 (c-kit(low)/CD30+/CD40+) cell lines: 'two-sided' model for investigating leukemic megakaryocytopoiesis. 930 12

Structural analysis of naturally processed peptides bound to the HLA class I and class II molecules of chronic myeloid leukemia (CML) blast cells was performed to characterize the antigen processing and autoantigen repertoire in this hematopoietic malignancy. Self-peptides derived from the carboxy-terminal end of the breakpoint cluster region (bcr) protein, as well as several differentiation stage- and tissue-specific self-antigens characteristic of early stages of myeloid differentiation, such as c-fes, c-pim, granulocyte-macrophage colony-stimulating factor receptor alpha chain, proteinase 3, and cathepsin G, were identified. A common characteristic of several of the high copy-number self-peptides identified in this study is the participation of their parent proteins in signal transduction or myeloid effector function. Because bcr-abl junctional peptides bind to a limited number of major histocompatibility complex (MHC) class I alleles, an effective peptide-based immunotherapy strategy for CML requires identification of further tumor-associated or tissue-specific peptide antigens binding to common MHC alleles such as HLA-A2. The differentiation stage- and tissue-specific MHC-bound peptides found in this study, as well as the naturally processed proteins from which they are derived, may represent autoantigens towards which T-cell responses may potentially be developed for immunotherapy of hematopoietic malignancies such as CML.
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PMID:Naturally processed tissue- and differentiation stage-specific autologous peptides bound by HLA class I and II molecules of chronic myeloid leukemia blasts. 938 12

CRKL is a 39 kDa adapter protein, originally cloned in proximity to the BCR gene on chromosome 22, which has a key regulatory role in hematopoietic cells. CRKL has one SH2 and two SH3 domains, with 60% homology to CRK II. CRKL is a prominent substrate of the BCR/ABL oncoprotein in chronic myelogenous leukemia and binds to both BCR/ABL and c-ABL. CRKL has been shown to be tryosine phosphorylated in response to normal hematopoietic growth factor receptor signaling with ligands such as thrombopoietin, erythropoietin or steel factor. Additionally, CRKL is involved in signaling initiated by crosslinking of beta integrins, and B cell or T cell receptors. Structurally, the amino-terminal SH3 domain of CRKL has been shown to bind proteins such as C3G, SOS, PI3-K, c-ABL or BCR/ABL. The SH2 domain of CRKL can bind to tyrosine phosphorylated proteins such as CBL, HEF1, CAS or paxillin. This review summarizes the current knowledge on the function of this unique adapter protein in normal hematopoietic and leukemic cell signaling.
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PMID:Role of the adapter protein CRKL in signal transduction of normal hematopoietic and BCR/ABL-transformed cells. 959 59

A novel Philadelphia chromosome-positive cell line was established from the peripheral blood of a patient with chronic myelogenous leukemia in megakaryoblastic crisis. This cell line, designated TN922 showed the positive phenotypes for myeloid, monocyte-macrophage, erythroid and megakaryocytic markers. The stimulation with phorbol 12-myristate 13-acetate (PMA) increased the expression of megakaryocytic markers including the platelet peroxidase activity, dimethylsulfoxide or transforming growth factor-beta promoted up-regulation of the erythroid markers. Stimulation with PMA, tumor necrosis factor-alpha or interleukin-6 also brought about the expression of monocytoid markers. These findings indicated that TN922 cell line has the property of acting as multipotential progenitor cells. TN922 cells showed gradual growth in the absence of growth factors but the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) promoted cell growth. The message of GM-CSF was detected in TN922 cells and the neutralizing antibody against GM-CSF receptor alpha-subunit suppressed cell growth. These results indicated that TN922 cell line proliferates in an autocrine secretion of GM-CSF.
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PMID:A novel Philadelphia chromosome-positive cell line with multipotential properties. 1022 66

Overcoming imatinib mesylate (IM) resistance and disease persistence in patients with chronic myeloid leukemia (CML) is of considerable importance to the issue of potential cure. Here we asked whether autocrine signaling contributes to survival of BCR/ABL+ cells in the presence of IM and nilotinib (NI; AMN107), a novel, more selective Abl inhibitor. Conditioned media (CM) of IM-resistant LAMA84 cell clones (R-CM) was found to substantially protect IM-naive LAMA cells and primary CML progenitors from IM- or NI-induced cell death. This was due to an increased secretion of the granulocyte-macrophage colony-stimulating factor (GM-CSF), which was identified as the causative factor mediating IM resistance in R-CM. GM-CSF elicited IM and NI drug resistance via a BCR/ABL-independent activation of the janus kinases 2 (JAK-2)/signal transducer and activator of transcription 5 (STAT-5) signaling pathway in GM-CSF receptor alpha receptor (CD116)-expressing cells, including primary CD34+/CD116+ GM progenitors (GMPs). Elevated mRNA and protein levels of GM-CSF were detected in IM-resistant patient samples, suggesting a contribution of GM-CSF secretion for IM and NI resistance in vivo. Importantly, inhibition of JAK-2 with AG490 abrogated GM-CSF-mediated STAT-5 phosphorylation and NI resistance in vitro. Together, adaptive autocrine secretion of GM-CSF mediates BCR/ABL-independent IM and NI resistance via activation of the antiapoptotic JAK-2/STAT-5 pathway. Inhibition of JAK-2 overcomes GM-CSF-induced IM and NI progenitor cell resistance, providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML.
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PMID:Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. 1709 Jun 51

Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage-CSF (GM-CSF) are the principal cytokines in granulopoiesis and differentiation of granulocytic precursors. Their physiologic effects are mediated by binding to specific cell surface receptors (G-CSFr and GM-CSFr, respectively), which are widely expressed from immature bone marrow cells to mature peripheral granulocytes. The fact that concentrations of plasma G-CSF and GM-CSF and their receptors are changed in infectious diseases showing neutrophilia is known, but such changes in patients with chronic myelogenous leukemia (CML) have not been studied. Based on quantitative assays of plasma G-CSF and GM-CSF and their receptors on the peripheral granulocytes of CML patients and healthy controls, this study analyzes the differences between these groups in G-CSF and GM-CSF levels, as well as quantitative and qualitative changes in the receptors. Plasma levels of G-CSF and GM-CSF were measured in 47 patients in the chronic phase of CML and 25 healthy adults as normal controls. G-CSFr and GM-CSFr on peripheral granulocytes were analyzed by quantitative flow cytometry, and changes in G-CSF and GM-CSF receptor counts were also measured. Plasma concentrations of G-CSF and GM-CSF in CML patients were similar to normal controls (p>0.05). The quantity of G-CSFr on neutrophils was more highly expressed than on other cell types in both groups, and the amount of this receptor in patients with CML was less than in normal controls (p=0.001). GM-CSFr was expressed in higher concentrations on monocytes than neutrophils, and there was no difference in the amount of GM-CSFr on neutrophils. After incubation with excess G-CSF, the expressed amounts of G-CSFr on neutrophils and monocytes were decreased in both groups. However, G-CSFr on the monocytes was decreased in healthy controls (p=0.02) with no difference in patients with CML. The quantities of GM-CSFr expression on neutrophils and monocytes after incubation with excess GM-CSF were decreased in both groups. Granulocyte counts in peripheral blood of CML patients were not correlated with the plasma concentrations of G-CSF or GM-CSF, nor with the expression of G-CSFr or GM-CSFr on granulocytes. Granulopoiesis in patients with CML was not mediated by increased plasma CSF concentrations, and there was no difference in the amounts of G-CSFr or GM-CSFr expressed on the granulocytes. This suggests that a structural change may occur on monocytes of CML patients, since the binding capacity of G-CSFr to G-CSF on the monocytes is different from the normal controls.
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PMID:G-CSF and GM-CSF concentrations and receptor expression in peripheral blood leukemic cells from patients with chronic myelogenous leukemia. 1898 25


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