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

Severe chronic neutropenia (SCN) is a rare but important cause of recurrent fevers, oropharyngeal ulcerations and severe infections. In three forms of SCN, i.e., congenital neutropenia (Kostmann's syndrome and related syndromes), idiopathic neutropenia (both childhood and adult), and cyclic neutropenia, it is now established that long-term treatment with the hematopoietic growth factor, recombinant human granulocyte colony stimulating factor (rHuG-CSF or Filgrastim), can elevate blood neutrophil counts to the normal range in most patients, with a concomitant reduction in infection-related events including fever, oral ulcerations, antibiotic use and symptoms of inflammation. Treatment with this growth factor causes an increase in the number and maturity of marrow cells of the neutrophilic series; other cell lines are largely unaffected. Marrow stimulation and expansion are reflected by the occurrence of bone pain early in therapy, as well as some increase in spleen size in most cases. Adverse effects of therapy are infrequent in both children and adults, and long-term treatment with daily or every-other-day s.c. injections of rHuG-CSF are well accepted. Because of the risk that some patients with chronic neutropenia may have or develop myelodysplasia and/or leukemia, careful pretreatment evaluations (blood, bone marrow and cytogenetics) and long-term observations are extremely important. An international registry for patients with SCN has been established to maintain records and further investigate these conditions.
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PMID:Hematopoietic growth factors for the treatment of severe chronic neutropenia. 778 81

Interleukin-3 (IL-3), a cytokine known to be produced by activated T lymphocytes, mast cells, eosinophils and neutrophils, is a potent stimulator of normal haemopoiesis, particularly megakaryocytopoiesis. However, it remains unknown whether leukaemic megakaryoblasts can produce IL-3 and whether IL-3 is involved in the pathological process of megakaryoblastic leukaemia. In this study, several human leukaemia cell lines with or without megakaryocytic features, the DAMI, MEG-01, HEL, K562, HL-60 and U937, were chosen as the models. It was first demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR) and indirect immunofluorescence assay that IL-3 was expressed in DAMI and MEG-01 cells, but not in other cell lines, although two erythroleukaemic cells, the HEL and K562, also possess some megakaryocytic features. Interestingly, the mRNA for IL-3 receptor was detected in nearly all the cell lines except K562 cells, suggesting that expression of IL-3 and its receptor may be dissociated in most of the cell lines and that co-expression of IL-3 and its receptor exists in megakaryoblastic cell lines, the DAMI and MEG-01. Of the cell lines which did not express IL-3 under unstimulated condition, only HEL cells were able to express IL-3 mRNA after treatment with PMA for 72 h. Furthermore, the proliferation of DAMI and MEG-01 cells could be enhanced in the presence of IL-3 and suppressed by the anti-IL-3 antibody and the IL-3 antisense oligodexyonucleotides (ODNs). These findings indicate that IL-3, as an autocrine growth factor, is involved in the growth of some megakaryocytic leukaemia cell lines.
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PMID:Interleukin-3 is an autocrine growth factor of human megakaryoblasts, the DAMI and MEG-01 cells. 781 61

v-mpl is a truncated form of a receptor-like chain which belongs to the cytokine receptor superfamily. This sequence has been transduced in the myeloproliferative leukemia virus as an env-mpl fusion gene responsible for an acute myeloproliferative disorder in mice. We constructed a series of viral mutants in the mpl sequence. Analysis of their oncogenic potential in vivo indicated that a critical 69-amino-acid-long cytoplasmic domain of v-Mpl is required for myoproliferative leukemia virus pathogenicity. We also developed an in vitro assay and showed that expression of the env-mpl gene confers growth factor independence to murine as well as to human hematopoietic growth factor-dependent cell lines. These findings strongly suggest that v-Mpl delivers a constitutive proliferative signal through a limited region of its cytoplasmic domain.
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PMID:Characterization of mpl cytoplasmic domain sequences required for myeloproliferative leukemia virus pathogenicity. 803 24

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have previously been reported to induce rapid phosphorylation of the mitogen-activated protein (MAP) kinase. However, little is known about signaling events initiated by both hematopoietins that occur downstream of the MAP kinase. MAP kinase has been shown to phosphorylate the AP-1 transcription factor and also to activate two kinases designated insulin-stimulated protein kinase-1 and MAP kinase-activated protein (MAP-KAP) kinase 2. We show here that IL-3 and GM-CSF induce MAPKAP kinase 2 activity in the human megakaryoblastic leukemia cell line MO7 and phosphorylate the human small heat shock protein Hsp 27 on serine residues in vitro. GM-CSF also induced Hsp 27 phosphorylation in neutrophils in a range similar to that observed in MO7 cells, suggesting that MAPKAP kinase 2-mediated Hsp 27 activation occurs independently of proliferation. Hsp 27 phosphorylation was dose-dependent, occurred as early as 5 minutes after factor exposure, and was inhibited by the tyrosine kinase inhibitors genistein and herbimycin A. Furthermore, the protein phosphatase A2 abolished IL-3- and GM-CSF-induced serine phosphorylation of Hsp 27. Taken together, our findings indicate that tyrosine phosphorylation of MAP kinase is a prerequisite for serine phosphorylation of Hsp 27, which is mediated by MAPKAP kinase 2. Hsp 27 has shown activation-dependent translocation from the cytosolic to the nuclear region and has been linked to the cellular stress response. However, its precise function is largely unknown. Our data identify Hsp 27 as a target of the IL-3/GM-CSF stimulation pathway that involves MAP kinase and MAPKAP kinase 2. In addition, our results indicate that Hsp 27 may be target of phosphorylation events not only in the stress response but also in unstressed cells responding to cytokine stimulation.
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PMID:Interleukin-3 and granulocyte-macrophage colony-stimulating factor induce activation of the MAPKAP kinase 2 resulting in in vitro serine phosphorylation of the small heat shock protein (Hsp 27). 1101 49

The FLT3 gene encodes a protein that appears to function as a receptor for a hematopoietic growth factor; together with the KIT and FMS receptors, FLT3 belongs to the superfamily of receptors with tyrosine kinase activity. We examined the expression of FLT3 mRNA in 36 human leukemia-lymphoma cell lines using Northern blot analysis. FLT3 transcripts were found in seven of seven pre B-ALL cell lines (derived from cases with pre B-acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast crisis), and in one of six B-cell lines (namely in a cell line established from a hairy cell leukemia). FLT3 message was not detected in five T-cell, five myeloid, four monocytic, four erythroid and five megakaryocytic cell lines. Two major mRNA species were expressed differentially by positive cell lines. KIT mRNA expression was also investigated in the same panel of cell lines, but was found only in cell lines with erythroid and megakaryocytic features (and not in any of the FLT3-positive cell lines). The pattern of expression of FLT3 contrasts with the transcription of FMS and KIT and suggests that the FLT3 product may play a role primary in immature lymphoid cells.
Leukemia 1994 May
PMID:Expression of the FLT3 gene in human leukemia-lymphoma cell lines. 818 45

The biological roles of cytokines and cytokine receptors were examined in acute lymphoblastic leukaemia cells expressing myeloid antigens (My+ ALL). Interleukin-3 (IL-3), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and low molecular-weight B-cell growth factor (LW-BCGF) could induce DNA synthesis in certain cases of My+ ALL. Whereas in My- ALL the stimulatory effects were shown only with LW-BCGF. Acute myelogenous leukaemia (AML) cells were activated with multiple cytokines including interleukin-1 (IL-1), IL-3, G-CSF and GM-CSF. Specific receptors for IL-1 and IL-3 were strongly expressed on both My+ and My- ALL cells. These receptors, however, were weakly detectable on AML cells. Additionally we studied the production of tumour necrosis factor-alpha and IL-1 by leukaemic blasts and found that distinct amounts of both cytokines were released from My+ ALL cells and AML cells, but not from My- ALL cells. The profiles of cytokines and cytokine receptors expressed by My+ ALL showed both similarities and differences to those in My- ALL or AML. The proliferation of My+ ALL cells was dependent on multiple cytokines that would regulate growth and maturation in a lineage-restricted fashion. These data suggested that My+ ALL cells might originate from uncommitted haematopoietic precursor cells coexpressing features of both lymphoid and myeloid lineages.
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PMID:Role in growth regulation of cytokines and cytokine receptors in acute lymphoblastic leukaemia expressing myeloid markers. 821 91

Current evidence suggests that the most primitive of hematopoietic progenitors detectable in adult human marrow are cells that can give rise to clonogenic cells for > 5 weeks in vitro when co-cultured with certain stromal cells. Procedures developed to isolate these so-called long-term culture-initiating cells (LTC-IC) in highly purified form allow their separation from most other hematopoietic cells as well as from stromal cells and their precursors also present in the marrow. We have used such procedures in conjunction with the LTC system to identify specific growth factors that support human LTC-IC maintenance and differentiation and to make comparisons with effects on later events in hematopoiesis. In some studies, soluble growth factors were added exogenously to the study cultures. In others, marrow-derived fibroblasts were genetically engineered to allow increased levels of specific human growth factors to be endogenously produced. In both of these ways, the influence of granulocyte--macrophage colony-stimulating factor (GM-CSF), G-CSF, Interleukin-3 (IL-3), IL-6, and Steel factor were investigated. Increased provision of GM-CSF alone (or in combination with other factors) enhanced terminal cell differentiation (production of granulocytes and macrophages), although the same conditions had no influence on LTC-IC differentiation (production of clonogenic cells) or on LTC-IC maintenance. In contrast, G-CSF, IL-3 and IL-6 alone (and more so when combined) in the presence of feeders effectively enhanced LTC-IC differentiation and was less active on later stages of granulopoiesis. Provision of additional exogenous Steel factor also enhanced LTC-IC differentiation, although Steel factor alone, without feeders or other growth factors, did not support either the initial differentiation of LTC-IC into clonogenic cells or their subsequent differentiation into mature granulocytes and macrophages. No combination of exogenously added growth factors was found that enhanced LTC-IC maintenance over that achieved with primary marrow feeders. However, some murine fibroblasts (including those of SI/SI origin), as well as certain exogenous growth factors (including Steel factor), were able to substitute for feeders in this regard. These observations highlight the likelihood of redundancy in factors that can elicit similar biological responses at the earliest as well as later stages of hematopoietic cell development. Nevertheless, it appears that the responses of hematopoietic cells at different stages of differentiation to any particular factor may differ markedly and that the nature of any particular response is not yet predictable from a knowledge of effects on earlier or later cell types.
Leukemia 1993 Aug
PMID:Growth factor regulation of the maintenance and differentiation of human long-term culture-initiating cells (LTC-IC). 836 Dec 14

Similar to two other hematopoietic growth factor receptors, the c-fms (macrophage colony-stimulating factor receptor) and the c-kit genes, c-mpl has been discovered through the study of oncogenic retroviruses. Unlike c-fms and c-kit, which both belong to a subgroup of tyrosine kinase receptors, the c-mpl proto-oncogene encodes a new member of the cytokine receptor superfamily. We have studied the expression of c-mpl in a series of 105 patients with hematologic malignancies using Northern blot analysis. The levels of c-mpl transcripts in lymphoid malignancies and in chronic myeloproliferative disorders were not significantly different from those found in normal bone marrow cells, in which c-mpl was barely detectable. In contrast, c-mpl expression was increased in 26 of 51 patients with acute myeloblastic leukemia (AML) and in 5 of 16 patients with myelodysplastic syndromes. Amplification of the c-mpl gene was detected in genomic DNA of one M4 AML patient. There was no significant correlation between c-mpl expression and the French-American-British classification of AML. Patients with high c-mpl expression appeared to belong to a subgroup of AML with a low rate of complete remission and a poor prognosis, including secondary leukemia and AML with unfavorable cytogenetic abnormalities.
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PMID:Expression of the c-mpl proto-oncogene in human hematologic malignancies. 839 55

Interleukin 3 (IL-3) is a multipotent hematopoietic growth factor which became available as a recombinant (rh) growth factor for use in the clinic a few years ago. In dose-finding studies, this hematopoietic growth factor has been evaluated without and after standard chemotherapy. Stimulatory effects on leukocytes, neutrophils, eosinophils, monocytes, reticulocytes and platelets were observed in some studies. Chemotherapy postponement due to insufficient bone marrow recovery was less frequent when IL-3 was administered. There are some clinical studies available in which rhIL-3 is combined with rh granulocyte-macrophage colony-stimulating factor (GM-CSF). The results do not clearly suggest superiority of these combinations over rhGM-CSF alone, but this may be partly due to the time scheduling of the growth factors. Administration s.c. is not inferior to i.v. Side effects mainly consist of flu-like symptoms and headache. The role of rhIL-3 after high-dose chemotherapy and autologous bone marrow reinfusion is still questionable. The addition of rhIL-3 to rhGM-CSF both administered after chemotherapy may allow a very high yield of peripheral stem cells suitable for bone marrow reconstitution after high-dose chemotherapy. rhIL-3 can stimulate leukemia tumor cell proliferation in vitro as well as proliferation of solid tumor cell lines. It is not yet clear in which way rhIL-3 combined with chemotherapy will effect tumor response and patient survival. It is too early to define the exact place of rhIL-3 in oncology. Additional studies with rhIL-3 alone and in combination with other growth factors are needed.
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PMID:Recombinant human interleukin 3 in clinical oncology. 845 87

To characterize the interactions between human T-cell leukemia virus (HTLV) infection and cellular gene expression, we examined the expression of the lymphokine interleukin 3 (IL-3) in the presence and absence of HTLV infection. IL-3, like granulocyte-macrophage colony-stimulating factor (GM-CSF), is produced by activated but not resting T cells, but although GM-CSF is constitutively expressed in HTLV-infected T cells IL-3 mRNA cannot be detected in either unstimulated or mitogen-stimulated HTLV-infected cells by polymerase chain reaction (PCR) analysis. In contrast, transient co-transfection studies with an IL-3 promoter-CAT reporter gene and an HTLV-II Tax expression construct demonstrate that Tax can transactivate the IL-3 promoter in HTLV-uninfected T cells. To determine whether differences in IL-3 promoter-binding proteins present in HTLV-infected and uninfected T cells account for this discrepancy, DNAase I footprinting of the IL-3 promoter was performed. Although crude nuclear extracts from both cell types protected the IL-3 sequences located between base pairs -168 and -125, the sequences between -125 and -103, which contain the lymphokine consensus sequences CK-1 and CK-2, were protected by extracts from HTLV-infected but not HTLV-uninfected T cells. Deletion of the region containing the CK-1 and CK-2 sequences from an IL-3 promoter CAT construct resulted in a sixfold rise in promoter activity in HTLV-infected but not uninfected T-cell lines, indicating that this region participates in the repression of IL-3 gene expression in HTLV-infected T cells.
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PMID:Differential effect of HTLV infection and HTLV Tax on interleukin 3 expression. 851 Sep 34


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