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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here experiments on the analysis of cellular signal transduction in a series of patients with chronic B cell disorders (B cell chronic lymphocytic leukemia [B-CLL] and prolymphocytic leukemia). We compared the response of the leukemic cells with primary external signals (interleukin 2 [IL-2] or B cell differentiation factors [BCDF or IL-6]) with their response to secondary inducers (the phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA] or the calcium ionophore A23187) that circumvent the first part of the signal transduction pathway by directly activating the key enzyme protein kinase C. One BCDF was synthesized by mitogen-activated peripheral blood B lymphocytes; a second BCDF was constitutively produced by the human bladder carcinoma cell line T24. Changes in morphology, Tac (IL-2 receptor) expression, RNA synthesis measured by 3H-uridine uptake, and immunoglobulin production tested by enzyme-linked immunosorbent assay were used as parameters of successful signal transduction. TPA alone and TPA plus A23187 (synergistically) effectively initiated differentiation in all the leukemia cases. Neither IL-2 nor BCDF (singly or in combinations) caused equivalent responses. On the other hand, IL-2 and BCDF produced a substantial differentiation effect on normal B lymphocytes. Our data suggest that (a) B-CLL cells are able to respond to direct stimulation of the second messenger pathway (through protein kinase C) but not to the physiological stimuli IL-2 or BCDF; (b) the defect in signal transduction appears to be located upstream of protein kinase C (a possible candidate is a G protein); (c) malignant B cells may spontaneously or after treatment with inducers express the IL-2 receptor (Tac antigen) in the absence of a functional differentiating response to IL-2; and (d) signs of proliferation/differentiation in B-CLL samples after incubation with IL-2 or BCDF might be due to contamination of the cell populations with residual normal B cells.
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PMID:Analysis of signal transduction in B chronic lymphocytic leukemia cells. 312 49

Tumor cells from 5 human B cell non-Hodgkin's lymphoma (B-NHL) patients were investigated for proliferative activity and idiotypic (Id+) immunoglobulin (Ig) secretion in serum-free medium without deliberate addition of B cell growth or differentiation factors (BCDF). These data were compared with cell surface marker expression, notably of activation antigens such as 4F2 and interleukin-2 (IL-2) receptor. Cells from all patients became 4F2 positive at the end of the 6-day culture period. Freshly drawn cells from 3 out of 5 patients expressed the IL-2 receptor (CD25; Tac antigen) or acquired this marker during culture in vitro and secreted relatively high levels of Id+ Ig in vitro. This correlated with elevated serum Id levels (greater than or equal to 0.5 micrograms/ml in vitro versus greater than or equal to 20 micrograms/ml in vivo). In the 2 CD25 (Tac)- B-NHL patients serum Id levels were below the detection limit and the amount of Id+ Ig secreted in vitro did not surpass 50 ng/ml. Only the B-NHL cells from a single patient were initially CD25 (Tac) positive and only these cells proliferated in serum-free culture. To test whether IL-2 receptor expression in the 3 CD25 (Tac)+ patients was functional, recombinant IL-2 (rIL-2) either alone or in conjunction with BCDF and recombinant IL-4 (rIL-4) was added to the cultures. In 2 out of 3 CD25 (Tac)+ patients rIL-2 was capable of enhancing proliferation or Ig secretion. In addition rIL-2 was found to enhance BCDF-mediated but not rIL-4 mediated responses. The third CD25 (Tac)+ B-NHL population was resistant to any of these lymphokines. Thus, this serum-free culture system may accurately reflect patient serum Id levels. IL-2 appears to regulate not only the in vitro but also the in vivo Ig secretion by neoplastic B cells.
Leukemia 1988 Apr
PMID:Idiotypic immunoglobulin secretion by human B cell non-Hodgkin's lymphomas is related to the expression of the interleukin-2 receptor. 312 22

The expression of transcripts of the c-myb and c-myc protooncogenes and the interleukin 2 receptor (IL-2R) gene in human T cells infected with human T-cell leukemia virus type 1 (HTLV-1) after exposure to interleukin 2 (IL-2) were examined. Infection with HTLV-1 is known to be associated with constitutive expression of IL-2R, although infected cells do not require IL-2 for growth. Northern blot analysis showed that expression of the mRNAs of the c-myb, c-myc, and IL-2R genes were markedly increased by addition of IL-2 into the cultures, indicating that IL-2R transduced signals for gene expression in these cells as in normal T cells. Studies on distinct HTLV-1-infected T cell clones that differed in numbers of high-affinity IL-2R, showed that the extents of increase in mRNA expression by IL-2 were correlated with the number of high-affinity IL-2R. This correlation was confirmed by demonstration that the levels of mRNA expression were proportional to the numbers of IL-2-bound high-affinity but not low-affinity receptors. Thus, the signals induced by IL-2 for gene expression may be through high-affinity IL-2R.
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PMID:High affinity interleukin 2 receptors in HTLV-1-infected T cells can mediate signals for gene expression. 350 78

A new mouse monoclonal antibody (HIEI, IgG1 type) that reacts with a cell surface glycoprotein of human lymphocytes was isolated. Membrane immunofluorescence assay showed that HIEI, like the anti-Tac monoclonal antibody, reacted preferentially with activated normal human T-cells and adult T-cell leukemia (ATL) virus (ATLV)-carrying human T- and B-cell lines. However, an interesting difference between HIEI and anti-Tac antibody was that HIEI did not react with ATLV-transformed simian cell lines or those cultured with interleukin-2 (IL-2), whereas the anti-Tac antibody did. The immunoprecipitation assay showed that both HIEI and anti-Tac antibody precipitated a glycoprotein with a molecular weight of 60,000 daltons (gp60) from activated normal T-cells and ATLV-positive T- and B-cells, and also gp53 from MT-2 and MT-2-related T-cell lines transformed with ATLV in vitro by the MT-2 cocultivation method. HIEI inhibited the IL-2-dependent proliferation of normal T-cells, but its inhibitory effect was much weaker than that of the anti-Tac antibody. The anti-Tac antibody interfered with the binding of HIEI to target cells, but HIEI did not block binding of the anti-Tac antibody to the cells. These observations indicate that HIEI antibody recognizes a new antigenic determinant of the human Tac antigen.
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PMID:A new monoclonal antibody recognizing an antigen of human lymphocytes similar or identical to Tac antigen. 608 38

The cell surface phenotypes of leukemic cells obtained from 30 patients with adult T-cell leukemia (ATL) were examined by means of a panel of OKT monoclonal antibodies and an anti-Tac monoclonal antibody. These leukemic cells were reactive with OKT1, OKT3, OKT4, OKT10, and OKT11 but not with OKT5, OKT6, OKT8 antibodies, suggesting that they were derived from peripheral mature cells included in the OKT4+ "helper/inducer" T-cell subset. Functionally, leukemic cells from none of the nine patients studied stimulated pokeweed mitogen (PWM)-driven immunoglobulin (Ig) synthesis by normal B cells. Suppressor cell activity, however, was found in 17 of 25 patients in PWM-induced Ig production. Fresh or cultured ATL cells from 22 of 23 patients tested expressed Tac antigen (interleukin-2 receptor) on the cell surface. The significance of Tac antigen on ATL cells is discussed in relation to the abnormal regulation of Tac antigen and leukemogenesis.
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PMID:Cell surface phenotype and in vitro function of adult T-cell leukemia cells. 609 84

We provide direct evidence for interleukin 2 receptor (IL2R) induction by human T-cell leukemia/lymphoma virus (HTLV) in human B-cell lines. A lymphoblastoid B-cell line (LCL-Ter) was established by Epstein-Barr virus-induced transformation of peripheral blood lymphocytes derived from a healthy HTLV carrier and cloned in vitro. HTLV gp21 and/or p19 antigens were detected in eight LCL-Ter clones, all of which also expressed the IL2R antigens Tac and Hiei (defined by monoclonal antibodies). However, five other LCL-Ter clones, which were negative for the HTLV antigens, did not express the IL2R antigens. Furthermore, when the IL2R-negative B-cell line LCL-Kan, derived form a normal donor, was cocultured with HTLV-producer cells, three HTLV-carrying clones were obtained and found to constitutively express IL2R. IL2R induced by HTLV on these B-cell lines bound recombinant interleukin 2 and were similar in apparent molecular mass (approximately equal to 60 kDa) to the IL2R of peripheral blood lymphocytes stimulated with phytohemagglutinin.
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PMID:Retrovirus-induced expression of interleukin 2 receptors on cells of human B-cell lineage. 609 96

Human T-cell leukemia/lymphoma virus type I(HTLV-I) infection appears to be closely associated with the leukemogenesis of adult T-cell leukemia (ATL), although its mechanism remains unclear. Since our previous report that leukemic cells from patients with ATL expressed Tac antigen (Ag) (interleukin-2 (IL-2) receptor) on their cell surface, we have been studying IL-2 receptors on ATL leukemic cells to see whether they are different from normal IL-2 receptors and whether they play a role in the neoplastic growth of ATL cells. Peripheral blood leukemic cells from 35 patients with ATL expressed IL-2 receptors which were detected by anti-Tac monoclonal antibody when examined immediately after the separation of cells or after culture for 24 or 48 hr. The number of anti-Tac binding sites ranged from 4,300 to 11,400 in fresh cells and from 6,100 to 96,000/cell in short term cultured leukemic cells, whereas phytohemagglutinin-P(PHA-P)-stimulated normal T cells exhibited 7,000 to 35,000 anti-Tac binding sites/cell. HTLV-I-infected cell lines such as MT-1 and HUT-102 expressed a markedly enhanced number of Tac Ag molecules. Leukemic cells from 15 ATL patients showed no or very poor proliferative response to various concentrations of IL-2, although they expressed Tac Ag. Radiolabeled IL-2 binding experiments revealed that ATL leukemic cells could bind IL-2 although the number of IL-2 binding sites was much less than that of anti-Tac binding sites. IL-2 receptors on ATL cells, unlike normal activated T cells, were not modulated (down-regulated) by anti-Tac antibody.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Abnormal expression of interleukin-2 receptor (Tac antigen) in adult T-cell leukemia. 610 Jun 43

Interleukin-2 (IL-2) is a lymphokine synthesized by some T cells following activation. Resting T cells do not express IL-2 receptors but receptors are rapidly expressed on T cells following the interaction of antigens, mitogens, or monoclonal antibodies with the antigen specific T-cell receptor complex. Using anti-Tac a monoclonal antibody that recognizes the IL-2 receptor, the receptor has been purified. The receptor is a 33 kdalton peptide that is post-translationally glycosylated to a 55 kdalton mature form. Mature receptors contain both N-linked and O-linked sugars and are both sulfated and phosphorylated. Using an oligonucleotide probe, based on the N-terminal amino acid sequence, cDNAs encoding this receptor have been cloned, sequenced and expressed. The addition of anti-Tac to in vitro culture systems blocks the IL-2 induced DNA synthesis of IL-2 dependent T-cell lines and inhibits soluble auto- and alloantigen induced T-cell proliferation. Furthermore, it prevents the generation of cytotoxic and suppressor effector T cells. The anti-receptor antibody also inhibits lectin stimulated immunoglobulin synthesis and the sequential expression of late appearing activation antigens on T cells. Normal resting T cells and most leukemic T-cell populations do not express IL-2 receptors however the leukemic cells of all patients with human T-cell leukemia/lymphoma virus (HTLV-I) associated, adult T-cell leukemia (ATL) examined expressed the Tac antigen. In HTLV-I infected cells the 42 kdalton long open reading frame (LOR) protein encoded in part, by the pX region of HTLV-I may act as a transacting transcriptional activator that induces transcription of the IL-2 receptor gene thus providing an explanation for the constant association of HTLV-I infection of lymphoid cells and IL-2 receptor expression. The constant display of large numbers of IL-2 receptors which may be aberrant in the ATL cells may play a role in the uncontrolled growth of these leukemic T cells. Patients with the Tac positive ATL are being treated with an anti-Tac monoclonal antibody directed towards this growth factor receptor.
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PMID:Interleukin-2 receptor expression in retrovirus associated adult T-cell leukemia. 610 Jun 44

The first half of this report describes direct evidence for the interleukin 2 receptor (IL-2R)-inducing ability of human T-cell leukemia/lymphoma virus (HTLV). When an Epstein-Barr virus (EBV)-transformed human B-cell line, LCL-Kan was infected with HTLV or transfected with plasmid DNA containing defective HTLV genome (long terminal repeat (LTR)-gag-pX-LTR), LCL-Kan cells were altered to express IL-2R which was indistinguishable from that of normal activated T cells. The second half of this paper reports that IL-2 could inhibit proliferation of HTLV-carrying T-cell lines which were spontaneously immortalized from IL-2-dependent cells or peripheral blood cells containing ATL leukemia cells. These results suggest that expression of IL-2R may be induced by HTLV in HTLV-transformed cells, where the IL-2R plays an important role in transduction of continuous cell growth signal.
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PMID:Human retrovirus-induced IL-2 receptors and their possible role in transduction of continuous cell growth signal. 610 Jun 45

The origin and exact stage of differentiation of the neoplastic cells that comprise hairy cell leukemia have remained uncertain. As Ig heavy and light chain genes must both undergo a DNA rearrangement during B-cell development but rarely do so within other hematopoietic lineages, we examined these genes in this leukemia. The neoplastic cells of all eight cases demonstrated rearranged heavy and light chain genes and, in two cases examined, contained the corresponding mRNA for heavy and light chain Ig. Consistent with this B-cell genotype, all cases displayed cell surface HLA-DR and B-cell-associated antigens. Unexpectedly, all cases demonstrated cell surface Tac antigen, which previously had been restricted predominantly to select T-cell malignancies and activated T cells. Prior studies suggested that the anti-Tac monoclonal antibody recognized a peptide associated with the binding of interleukin 2 (T-cell growth factor) in such T cells. Immunoprecipitation with anti-Tac and NaDodSO4/polyacrylamide gel electrophoresis revealed an antigen on leukemic hairy cells with a Mr of 53,000-57,000, identical in size to the receptor on activated T cells. This apparent biphenotypic status might reflect a transformation-associated expression of the Tac antigen in this leukemia. Alternatively, hairy cell leukemia may be a malignancy of a unique stage of normal B-cell differentiation in which the Tac antigen is expressed.
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PMID:Rearrangement and expression of immunoglobulin genes and expression of Tac antigen in hairy cell leukemia. 619 35


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