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)

Monoclonal antibody YB5.B8 was previously shown to inhibit haemopoietic colony formation in response to a complex growth factor supplement in vitro (Cambareri A. C., Ashman L. K., Cole S. R. & Lyons A. B. (1988), Leukemia Res. 12, 929). We now report studies of the effect of the antibody on colony formation by normal human bone marrow cells in response to recombinant human colony-stimulating factors GM-CSF, G-CSF and IL-3. MAb YB5.B8 significantly reduced the yield of colonies of all types examined (granulocyte-macrophage, granulocyte, macrophage and eosinophil) in response to GM-CSF but not to IL-3 or G-CSF. However, MAb YB5.B8 failed to influence the proliferation of the myelomonocytic leukaemia cell line RC-2A in response to GM-CSF, G-CSF or IL-3. Direct binding studies demonstrated the presence of low numbers of receptors for GM-CSF on RC-2A cells, however, the binding of this cytokine was not influenced by co- and/or pre-incubation with MAb YB5.B8. Therefore the antigen identified by YB5.B8 is probably not a receptor for GM-CSF and may indirectly influence the response of normal haemopoietic progenitors to this cytokine.
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PMID:A monoclonal antibody that inhibits the action of GM-CSF on normal but not leukaemic progenitors. 169 6

A syndrome characterized by severe immunodeficiency and lymphoproliferation develops in susceptible strains of mice infected with a mixture of murine leukemia viruses (MuLVs) designated LP-BM5 MuLV. The etiologic agent in this mixture has been shown to be a replication-defective virus (BM5d) with a 4.8-kb genome that required replication-competent helper viruses, primarily ecotropic (BM5e), for cell-to-cell spread in the host. In the present study, we studied the expression of BM5d and BM5e in tissues of infected mice at various times after inoculation in relation to the expression of cytokine genes that may contribute to the pathogenesis of this disorder. Northern (RNA) analysis of total RNA showed that BM5d was expressed at significant levels in lymphoid tissues within 1 week of infection and that the levels of expression increased with time after inoculation. By 16 weeks postinfection, BM5d was expressed in all tissues examined. Expression of BM5e was relatively more restricted to lymphoid tissues and was detected at lower levels than expression of BM5d at early times after infection, but this virus was expressed in all tissues by 16 weeks. Infection with the virus mixture was associated with constitutive expression of tumor necrosis factor in all tissues examined and of interleukin-1 (IL-1) in lymphoid tissues within 1 week of infection, and at later times with widespread expression of these cytokines and gamma interferon. Also, the levels of interferon regulatory factor 1 mRNA were significantly increased in all infected tissues during the infection. In contrast, expression of IL-3, IL-4, IL-5, and IL-6 was not detectable by Northern analysis of the respective mRNAs in any infected tissue at early or late times postinfection.
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PMID:Expression of defective virus and cytokine genes in murine AIDS. 170 43

The controversial role of interleukin-6 (IL-6) as an auto- or paracrine growth factor for human multiple myeloma (MM) cells was studied using a panel of six well characterized feeder-cell dependent and independent MM cell lines as models. With respect to the effect of IL-6 on growth and survival, three types of lines were found: (1) U-1958, dependent on IL-6 both for growth and survival; (2) U-1996, dependent on IL-6 for growth but not survival; and (3) U-266-1984, Fravel, L363, and Karpas 707, independent of IL-6. Feeder-cell supernatants were as efficient as feeder-cell monolayers in stimulating growth and contained IL-6 as the only growth promoting activity. IL-6 was growth stimulatory and sustained the growth of U-1958 only when the medium contained fetal calf serum. The nature of the serum factor(s) is unknown, but it was excluded to be the IL-6 carrier protein a2-macroglobulin. IL-1, IL-2, IL-3, TNF-alpha, GM-CSF, IGF-1, and insulin were neither co-stimulatory with IL-6 nor stimulated growth on their own. Only U-266-1984 expressed IL-6 mRNA. IL-6 receptor mRNA was expressed in all lines except the L363 and Fravel. We conclude that the response to IL-6 is heterogeneous among the MM lines and that IL-6 acts as a paracrine growth factor for two of six lines. In a third line, U-266-1984, the IL-6 mRNA expression suggests the possibility of an autocrine growth stimulation.
Leukemia 1991 Mar
PMID:Heterogeneity in response to interleukin 6 (IL-6), expression of IL-6 and IL-6 receptor mRNA in a panel of established human multiple myeloma cell lines. 170 69

Differentiation of a human eosinophilic leukemia cell line, EoL-1, induced by the culture supernatant of a human ATL cell line, HIL-3 (HIL-3 sup) was compared with differentiation induced by defined cytokines. HIL-3 sup induced EoL-1 cells to express eosinophilic granules and segmented nuclei after 6 to 9 days of incubation. HIL-3 sup also induced the expression of Fc epsilon receptor II (Fc epsilon RII/CD23) and an eosinophil differentiation antigen EO-1 mainly on eosinophilic granule (+) cells. Furthermore, HIL-3 sup induced EoL-1 cells to respond to an eosinophil chemotactic factor, platelet activating factor. HIL-3 cells express messenger RNA (mRNA) of interleukin-5 (IL-5), macrophage colony-stimulating factor (M-CSF), and IL-3 but not granulocyte CSF (G-CSF). Granulocyte-macrophage CSF (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were detected in the HIL-3 sup. Recombinant IL-2 (rIL-2), rIL-3, rIL-4, rIL-5, rM-CSF, and rGM-CSF did not induce eosinophilic granules. rG-CSF induced a few eosinophilic granule (+) cells, and TNF-alpha, which did not induce eosinophilic granules by itself, enhanced the ability of G-CSF to induce them. However, G-CSF and TNF-alpha did not induce the expression of Fc epsilon RII and EO-1 antigen. Moreover, anti-G-CSF, anti-TNF-alpha, anti-GM-CSF, anti-IL-3, and anti-IL-5 antibodies did not suppress the effect of HIL-3 sup on the differentiation of EoL-1 cells. All the data suggest that HIL-3 sup contains an unidentified factor that induces differentiation of EoL-1 cells, and that EoL-1 cells and HIL-3 sup provide an important model for the examination of differentiation mechanisms and functions of eosinophils.
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PMID:Differentiation of a human eosinophilic leukemia cell line (EoL-1) by a human T-cell leukemia cell line (HIL-3)-derived factor. 170 98

The effects of human recombinant colony-stimulating factors (r-CSFs), interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on inducing the growth of colonies derived from patients with acute myeloid leukemia (AML) (CFU-L) were investigated and compared to the proliferative response of CFU-GM derived from highly enriched normal blast cell populations. The effects of GM-CSF and IL-3 alone were similar. Both only minimally stimulated normal colonies derived from CFU-GM when compared to stimulation with MoCM (a mean of 28% of the total colonies and 17% of the colonies greater than 100 cells obtained with MoCM). Similarly, the number of leukemic colonies was substantially less than with MoCM (less than 30% of MoCM) in all but 3/10 AML patients and both were only able to significantly stimulate CFU-L derived colonies greater than 50 cells from 2/10 patients. G-CSF alone stimulated some CFU-L derived colony growth in 9/10 patients but the number stimulated was minimal relative to MoCM in five of the patients and significant stimulation of colonies greater than 50 cells occurred in only one patient. The mean number of normal CFU-GM derived colonies stimulated by G-CSF was 41% of the total colonies and 34% of the colonies greater than 100 cells generated by MoCM. The combination of G-CSF with GM-CSF and G-CSF with IL-3 resulted in a synergistic or additive increase in the number of CFU-L in 5/10 and 7/10 patients, respectively, and a synergistic increase in the size of CFU-L in 5/10. The same combinations resulted in a significant synergistic effect on size of normal CFU-GM derived colonies. There was no evidence of a synergistic increase in the number or size of CFU-L and CFU-GM derived colonies stimulated with GM-CSF in combination with IL-3. In addition, a combination of all three (G-CSF + GM-CSF + IL-3) did not enhance the effect of G-CSF + GM-CSF or G-CSF + IL-3. These results suggest that there is significant heterogeneity among AML patients in the pattern of responsiveness of the leukemic cells to the recombinant growth factors. In addition, their responsiveness does not significantly differ from that of normal progenitors. In view of the current clinical trials with r-CSFs and cytotoxic drugs in AML patients, this issue is important and worthy of further investigation.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1991 May
PMID:Proliferative response of human acute myeloid leukemia cells and normal marrow enriched progenitor cells to human recombinant growth factors IL-3, GM-CSF and G-CSF alone and in combination. 170 11

The c-kit proto-oncogene encodes a transmembrane receptor with a tyrosine kinase internal domain. C-kit has been mapped to the W locus in the mouse, and the gene encoding the ligand has been shown to be the product of the murine SI locus. Previous genetic studies have shown that the murine W and SI loci play important roles in the normal function of hemopoietic stem cells. As these stem cells have been identified as the origins of abnormal clones in acute myeloblastic leukemia (AML), a study was begun of c-kit in AML. By Northern blot analysis, it was shown that all of 21 blast populations from AML patients were kit expression positive, but some AML cell lines did not transcribe detectable c-kit mRNA. This study is now extended to the responses of freshly obtained AML cells and cell lines to the ligand, mast-cell growth factor (MGF). In culture, fresh cells usually responded to added ligand with increases in both self-renewal and terminal divisions. The most obvious effects were seen when MGF was combined with either IL-3 or G-CSF. The response of cell lines to MGF mirrored their expression of c-kit; expression positive lines responded in culture with patterns similar to those seen for fresh cells. C-kit expression negative cells did not respond to MGF. RNA prepared from the cells giving rise to one such line, OCI/AML-5, was available for study. mRNA for c-kit could not be detected in this RNA sample by Northern blot analysis or the polymerase chain reaction. Thus the heterogeneity found in AML blast populations extends to the involvement of c-kit and its ligand in growth regulation, although blast populations without this regulatory apparatus appear to be rare.
Leukemia 1991 Jun
PMID:Mast cell growth factor, a ligand for the receptor encoded by c-kit, affects the growth in culture of the blast cells of acute myeloblastic leukemia. 171 40

The effects of human recombinant interleukin 4 (rIL-4) on the growth of leukaemic blast progenitors were investigated. Cells obtained from 20 acute myeloblastic leukaemia (AML) patients were evaluated using the blast colony assay in methylcellulose and suspension cultures. While rIL-4 by itself did not show any colony stimulatory activity in the blast colony assay, it suppressed the blast colony formation in methylcellulose stimulated with G-CSF, GM-CSF or IL-3 in 14 patients. In another six patients, rIL-4 enhanced blast colony growth in four patients or did not show any significant effect with any CSF in two patients. In suspension cultures of 12 cases studied, the effects of rIL-4 on the clonogenic cell recoveries were essentially similar to the results of the blast colony assay in each case. In three patients, rIL-4 augmented the differentiation of the leukaemic cells to monocyte lineage. Further, the clinical outcome was significantly different between the patients whose blast progenitors were stimulated by rIL-4 and the patients whose blast progenitors were suppressed by rIL-4 (P less than 0.05); three out of four patients in the former group failed in achieving complete remission (CR), while 12 out of 14 patients in the latter group achieved CR. The results show that the effects of IL-4 on leukaemic blast progenitors were diverse and the responsiveness to IL-4 may be correlated with the prognoses of the patients.
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PMID:Effects of recombinant interleukin 4 on the growth and differentiation of blast progenitors stimulated with G-CSF, GM-CSF and IL-3 from acute myeloblastic leukaemia patients. 171 23

Among 52 patients diagnosed as acute myeloid leukemia (AML), nine cases were found in which interleukin-5 (IL-5) induced a proliferative response in the leukemic cells, as measured by the stimulation of DNA synthesis or colony formation in vitro. All cases (n = 7) with the cytogenetic abnormality t(8;21)(q22;q22) belonged to this group of IL-5 responders. Of the additional two cases, one had an apparently normal karyotype, but the other expressed a dicentric chromosome 21, an abnormality also involving the breakpoint region 21q22. The leukemic cells of the IL-5 responsive patients could also be stimulated to proliferate by IL-3, GM-CSF and G-CSF, and in some cases by IL-6 or M-CSF. Immunophenotypic analysis revealed the presence of the immature hematopoietic cell antigen CD34, the myelomonocytic maturation antigens CD13 and CD33, in association with the B-cell related surface marker CD19 on the leukemic cells. Immunoglobulin mu and T-cell receptor beta-genes in the leukemic cells were in germline configuration. Upon incubation in colony culture, clonogenic cells were capable of producing progeny showing eosinophilic or neutrophilic maturation following stimulation with IL-5 or G-CSF, respectively. It is concluded that IL-5 responsive AML represents a subgroup of leukemia with distinct immunotypic and cytogenetic features.
Leukemia 1991 Aug
PMID:Acute myeloid leukemias with chromosomal abnormalities involving the 21q22 region identified by their in vitro responsiveness to interleukin-5. 171 59

The blast cells of acute myeloblastic leukemia (AML) usually require growth factors for optimum proliferation in cell culture. Growth factors also affect the sensitivity of AML blast cells to cytosine arabinoside (ara-C). Others have reported that factor-treated cells are more ara-C sensitive than blasts in culture without factors. These authors have reported previously that AML blasts grown with rG-CSF, with or without GM-CSF, are more sensitive than cells in GM-CSF alone. This paper reports experiments which show that changes in the ara-C sensitivities of blast cells in different growth factors are not explained by changes in the percentage of cells in the DNA synthesis (S) phase of the cycle. Blasts freshly obtained from five AML patients were cultured in either rG-CSF, rGM-CSF, or rIL-3; they were then exposed to 20 min pulses of either high specific activity tritiated thymidine (3HTdR) or a high concentration of ara-C. Regardless of the factor present, the pulse of 3HTdR decreased the number of clonogenic cells by about 50%, the result expected for actively proliferating cells with an S phase occupying about half the cycle time. The same result was found for four of the five blast cell populations grown in G-CSF and pulsed with ara-C; in contrast, clonogenic cells grown in GM-CSF or IL-3 from these four populations were not killed by ara-C. The blasts from the fifth patient were ara-C resistant under all conditions. It was concluded that exposure to GM-CSF or IL-3 decreased ara-C sensitivity in blasts that were actively making DNA. The observation was explored in more detail using a cell line (OCI/AML-1a) that is both ara-C sensitive and growth factor dependent. These studies showed that about 15 h of growth in factor are required for a change in ara-C sensitivity.
Leukemia 1991 Sep
PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 protect leukemic blast cells from ara-C toxicity. 171 8

By using antisense oligomers the functional role of the c-abl proto-oncogene in the in vitro growth of bone marrow hematopoietic progenitors from normal subjects and patients with chronic myelogenous leukemia (CML) has been evaluated. Light density bone marrow cells (LDBMs) were depleted of adherent cells, pre-incubated for 15 h with the appropriate oligomer at a concentration of 14 microns, and then plated in methylcellulose for the evaluation of colony formation. Both anti-exon Ia and anti-exon Ib antisense oligomers produced a significant inhibition of normal day 14 CFU-GM growth in vitro (n = 5, 41 +/- 11%, and 36 +/- 7%, respectively; p less than 0.01). In contrast, normal BFU-E growth was not significantly influenced by antisense oligomers (n = 5, 14 +/- 21% and 7 +/- 19%, respectively; p less than 0.05). These findings were confirmed by plating CD34 positive progenitors. When interleukin 3 (IL-3) (100 ng/ml) was added to the culture medium during the preincubation of LDBMCs, the inhibitory effects of antisense oligomers on normal CFU-GM growth were abolished. Seven patients with CML were also studied, all of whom had cytogenetic evidence of 100% clonal hematopoiesis. In five patients in the chronic phase, antisense oligomers were inhibitory on in vitro growth of both day 14 CFU-GM (37 +/- 20% and 37 +/- 15%, p less than 0.05) and BFU-E (45 +/- 15% and 41 +/- 11%, p less than 0.05), and this inhibition was not removed by pre-incubation with IL-3. No significant effect was observed on cluster or colony formation in two patients with CML in accelerated or blastic phase, and on in vitro growth of clonogenic cells from the Ph1-positive K-562 cell line. These findings (i) confirm previous observations showing a lineage specific requirement of c-abl function in normal hematopoiesis, and (ii) suggest that the residual c-abl expression has a role in chronic phase CML hematopoiesis, as its inhibition impairs both myeloid and erythroid colony formation in vitro.
Leukemia 1992 Jan
PMID:c-abl function in normal and chronic myelogenous leukemia hematopoiesis: in vitro studies with antisense oligomers. 173 9


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