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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukemia (AML) cells express the surface adhesion proteins intercellular adhesion molecule-1 (ICAM-1, CD54) and lymphocyte function associated molecule-3 (LFA-3, CD58). Exposure to the myeloid growth-promoting cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulates expression of ICAM-1 and LFA-3 on AML cells but does not increase their sensitivity to lysis by interleukin-2-activated natural killer cells (LAK) in 51Cr assays. However when AML cells are exposed to GM-CSF prior to incubation with LAK, their subsequent clonogenic activity is significantly reduced. If a blocking antibody to ICAM-1 is added during the incubation period of AML with LAK, the inhibitory effect is completely ablated. A less pronounced effect is observed with an antibody to LFA-3. ICAM-1 is expressed on a greater proportion of CD34+ than CD34- AML cells and exposure to GM-CSF induces a significantly greater upregulation of ICAM-1 on leukemic CD34+ cells than their CD34- counterparts. These data suggest that the inhibitory effect of IL-2-activated natural killer cells on clonogenic AML cells is mediated principally via the lymphocyte function associated molecule-1 (LFA-1)/ICAM-1 interaction. Interleukin-2 upregulates LFA-1 expression on natural killer cells. Simultaneous administration of effector cell activators such as IL-2 and target cell modulators such as GM-CSF may have a therapeutic benefit in patients with minimal residual myeloid leukemia.
Leukemia 1995 Apr
PMID:GM-CSF enhances IL-2-activated natural killer cell lysis of clonogenic AML cells by upregulating target cell expression of ICAM-1. 772 3

The immune response to leukemia is poorly understood. We postulated that nonmalignant T lymphocytes remaining within bone marrow from children with newly diagnosed ALL could be involved in this immune response. T lymphocytes which expressed gamma delta TCR comprised less than 1% of ALL marrow cells. A preferential outgrowth of gamma delta T cells within the CD3 population was observed when marrow cells were cultured with IL-2 alone or with stimulating feeder cells. These results, obtained in a series of 14 patients with precursor B-ALL, were significantly different when compared with expansions from normal marrow cells. In one patient, the clones established from the expanded population displayed different patterns of cytotoxicity against tumoral targets of the B cell lineage. Some clones expressing the TCR V delta 1 segment showed cytotoxic activity against a cell line derived from a pre-B ALL without activity against a LAK-sensitive B cell line. Using PCR amplification, one such clone was detected at high frequency, in the primary expansion of ALL marrow cells. These results suggest a prior activation in vivo of some gamma delta T cells by leukemic cells and provide some evidence on the role of these subsets in the immune response to leukemia.
Leukemia 1995 May
PMID:Potential antileukemic effect of gamma delta T cells in acute lymphoblastic leukemia. 776 50

We report the in vitro suppression of the IL-3-dependent MO-7 acute myeloid leukemia proliferation by an interleukin-3 antagonist. The antagonist was generated by alkylation to inactivate catalytic His-residues of native human interleukin-3. The resulting inhibitor caused a factor 7 inhibition of the growth-response curve of the IL-3 control-stimulated proliferation of a MO-7 leukemia cell line. A 40% inhibition of the MO-7 proliferation could be achieved with a partially alkylated inhibitor in presence of a factor 30 excess of native IL-3. Therefore, the inhibitor had a substantially improved affinity for the IL-3 receptor on these leukemia cells. At a concentration of as low as 0.1 ng/ml it still caused a 2-fold inhibition of the native IL-3-stimulated proliferation response curve. Thus it can be concluded that this alkylate IL-3 is a potent IL-3 antagonist. Based on the reported specific zinc binding of IL-2, IL-6, GM-CSF and gamma-interferon this suggests that more leukemias and even other forms of cancer can be effectively suppressed by alkylated growth factors.
Leukemia 1995 May
PMID:In vitro suppression of leukemia by alkylated interleukin-3. 776 58

Hairy-cell leukemia (HCL) is a B-cell leukemia, but many factors argue for a T-cell dysfunction and/or involvement in this disease. Hairy cells typically home in the spleen, and become circulating only late in the disease. As it is assumed that the T-cell abnormalities are caused by specific interactions with the hairy cells, we studied the immunophenotype in 17 cases (CD3, CD4, CD8, CD45R0, TCR gamma delta) and cytokine gene expression in four cases (IL-1 beta, IL-2, IL-3, IL-4, IL-6, IL-7, IL-10, IFN-gamma, TNF-alpha, GM-CSF and the receptors of IL-1 and IL-2, using the cDNA-PCR technique) of purified T-cell fractions from hairy-cell spleens. By Northern blot analysis, mRNA for IFN-gamma, GM-CSF, IL-10 and TNF-alpha was measured in purified T cells and hairy cells from three HCL spleens. The results of the immunophenotype and cDNA-PCR data were compared with ten normal spleens. Compared to blood, splenic T cells showed a reversed CD4/CD8 ratio, a normal percentage of memory T cells, and an increase in CD3+TCR gamma delta + cells. Without specific induction spontaneous cytokine gene expression of IL-2, IL-4, IFN-gamma, and GM-CSF was seen in the purified T-cell fractions without signals in the purified hairy-cell fractions. mRNA expression of IFN-gamma and GM-CSF in the T cells, and of IL-10 and TNF-alpha in the hairy cells was confirmed by the Northern blot technique. From these data we suggest that splenic T cells in HCL should not be considered as residual or recirculating T cells, but rather as tumor-infiltrating lymphocytes.
Leukemia 1994 Dec
PMID:Abnormally activated T lymphocytes in the spleen of patients with hairy-cell leukemia. 780 97

Administration of cytokines to patients with leukemia or lymphoma may recruit dormant malignant cells into cell cycle and thus make them more susceptible to chemotherapy. We treated a patient with refractory T cell acute lymphoblastic leukemia (ALL) with OKT3 monoclonal antibody and observed a dramatic but transient decrease of lymphoblasts. The T ALL cells were rather mature by morphology and immunophenotyping, expressing CD7, CD4, CD8 and CD3 surface antigens and nuclear TdT. Cytogenetic analysis revealed inversion of chromosome 14(q11q32.1). A total of 500 mg OKT3 (maximum dose 50 mg/day) was given. A decrease of lymphoblasts in the blood and a reduction of spleen size was observed. Complement levels dropped remarkably. Despite increasing serum levels of tumor necrosis factor, treatment was well tolerated overall. CD3 therapy induced strong IL-2 responsiveness of the lymphoblasts. Thus, OKT3 antibody treatment not only significantly decreased CD3-positive tumor cells, but also induced IL-2-mediated proliferation. This may also allow sequential application of CD3 and IL-2 to render certain T cell tumors more susceptible to chemotherapy.
Leukemia 1995 Mar
PMID:Therapy with OKT3 monoclonal antibody in refractory T cell acute lymphoblastic leukemia induces interleukin-2 responsiveness. 788 36

Cell lines of myeloid origin have been shown to express interleukin-2 receptors (IL-2R). Here, we demonstrate the expression of IL-2R alpha and IL-R beta on the CML blast cell line K562 by FACS analysis and cross-linking assay. Furthermore, we examined the effect of IL-2 on leukemic progenitor growth, employing K562 as a model. Clonogenic growth was assessed after 3 days of culture by colony formation in a serum-free, semi-solid assay system. IL-2 was found to exhibit a dose-dependent suppressive effect on K562 clonogenicity with 48% inhibition of colony formation at 250 U IL-2 and 60% inhibition at 1000 U IL-2. Philadelphia chromosome (Ph)-positive K562 cells possess multiple copies of the bcr/abl fusion gene whose transcript and protein product (p210) is thought to confer growth advantage to CML cells. We therefore investigated IL-2-dependent modulation of bcr/abl mRNA accumulation and p210 protein levels in K562 cells. After 4 h of culture in the presence of IL-2, a 3-15-fold reduction of bcr/abl mRNA accumulation was demonstrated by competitive reverse PCR. Reduction of bcr/abl fusion protein levels was demonstrated at 24 h of IL-2-supplemented cell culture, employing p210 recognizing monoclonal antibodies (mAbs) in FACS analysis. Levels of proliferation marker Ki67 were only marginally affected. We conclude: (1) K562 cells express both IL-2R alpha and IL-R beta; (2) IL-2 inhibits clonogenic growth of K562 in a dose-dependent manner; and (3) IL-2-mediated inhibition of K562 proliferation is preceded by a reduction of bcr/abl mRNA accumulation and p210 protein levels.
Leukemia 1995 Mar
PMID:IL-2 inhibits proliferation of K562 cells and reduces accumulation of bcr/abl mRNA and oncoprotein. 788 40

Isolated leukemic B cells from patients with B-chronic lymphocytic leukemia (B-CLL) were tested for proliferative response in vitro to Staphylococcus Aureus strain Cowan 1 (SAC), IL-2, and low molecular weight (MW) BCGF. Patients were classified according to clinical stage and progressiveness. Ten of eighteen cell populations from patients with progressive B-CLL responded in vitro with a stimulation index (SI) > 20. Only 1/16 non-progressive patients had a proliferative but low response. Normal unfractionated tonsillar B cells responded to SAC and BCGF, whereas normal high buoyant density B cells were unresponsive. After 3 days of stimulation, responding B-CLL cells had multiplied and the B cells expressed CD5, CD19, and weakly CD21. No cells in the responding cultures exhibited CD3 or the EBV nuclear antigen EBNA-1. Cell maturation, measured as IgM secretion, was found in some, but not in all responding B-CLL cultures. Thus, B-CLL cells from patients with progressive disease have the capacity to respond to signaling through surface Ig receptors and to certain T-cell factors which was not the case for B-CLL cells from non-progressive patients. The pattern of in vitro response may be related to disease progression, reflecting a dependency of normal immunoregulatory mechanisms and/or a dysregulation of the growth control in the leukemic cells.
Leukemia 1994 Jul
PMID:Leukemic cells from progressive B-CLL respond strongly to growth stimulation in vitro. 803 6

High-dose recombinant human Interleukin-2 was given to 21 patients with acute myeloid (n = 11) or lymphoid (n = 10) leukemia in relapse. A rapid decrease in the peripheral leukemic blasts numbers was observed in six patients. We were unable to demonstrate at the bone marrow level a diminution in the percentage of leukemic blasts. However an increase in the expression of the adhesion molecule CD54/ICAM-1(LFA-1 ligand) affected the leukemic bone marrow blasts of these six patients. This increase in CD54 was found in eight of the 11 (73%) AML and four out of the ten (40%) ALL blasts and CD58/LFA-3 (CD2 ligand) to a lesser extent. This increased expression was not associated with modifications in the expression of MHC class II molecules. In vivo IL-2 also dramatically modified the bone marrow T-cell subsets via the increase of CD3+ cells expressing the CD45RO 'memory' marker (six out of the eight tested patients) or CD54 (seven out of the eight tested patients). Altogether these results demonstrate that leukemic blasts can be affected by in vivo IL-2 via mechanisms that could involve T cells.
Leukemia 1994 Jul
PMID:Modifications of leukemic blast cells induced by in vivo high-dose recombinant interleukin-2. 803 17

The expression and function of IL-2R chains expressed on B-cell chronic lymphocytic leukemia (B-CLL) cells were analyzed. IL-2R alpha was expressed in 31 out of 34 studied cases; in 17 cases more than 50% of the cells were positive whereas in three cases the proportion of IL-2R alpha+ cells was less than 10%. In two patients, 6 and 13% of the cells were IL-2R beta+, in six other cases only 2-3% of the B-CLL cells could be stained with the TU-27 moAb whereas in all other cases no positive cells could be detected. Equilibrium binding experiments using 125I-rIL2 revealed high (seven out of 15 studied cases), intermediate (four out of 15 cases) and low (five out of 15 cases) affinity IL-2R. The number of high and intermediate affinity IL-2R was low (range: 145-800 and 40-2800 binding sites/cells, respectively). In all cases investigated, both IL-2R alpha and IL-2R beta chain mRNA could be detected, although their quantity was variable from patient to patient. Exogenous recombinant IL-2 induced, in a dose-response manner, cell proliferation in ten out of 23 cases and this effect was independent of the expression of IL-2R alpha; however, only cells expressing high affinity IL-2R could respond to exogenous rIL-2. Moreover, anti-IL-2R alpha moAb could inhibit both spontaneous (in three out of five cases) and IL-2-induced (in five out of five cases) B-CLL cell proliferation. These findings demonstrate that in a subgroup of B-CLL, leukemic cells are dependent on the IL-2/IL-2R system whereas in another group, although cells expressed functional IL-2 binding sites, they could not respond to the mitogenic signal of IL-2.
Leukemia 1994 Sep
PMID:Characterization of interleukin 2 receptors on B-cell chronic lymphocytic leukemia cells. 809 33

We studied the in vitro differentiation (immunoglobulin production) of purified malignant B cells of 21 patients with different B-cell malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HCL) and non-Hodgkin lymphoma (NHL). Direct activation of purified malignant B cells with phorbol myristate acetate (PMA) resulted in the differentiation of most CLL cells, but not of the other types of B-cell malignancies. This differentiation required the presence of interleukin 4 (IL-4). In contrast, with the use of anti-CD2-stimulated normal T cells and IL-2, immunoglobulin M (IgM) could be detected in the supernatant of all but one of the purified malignant B-cell populations. However, by analysis of the light chains of the IgM produced, monoclonality could be demonstrated in only 13/21 cases: 8/11 CLL, 3/3 PLL, 0/3 HCL, and 2/4 NHL. In two patients additional proof that the malignant B cells were the source of the IgM production could be obtained in an idiotype-specific ELISA. Apart from IgM, also the production of IgG antibodies could be detected. However, only for 2/3 HCL patients, we could confirm a monoclonal IgG production. Since HCL is a malignancy of mature B cells, already carrying IgG on the membrane, this IgG production is not the result of a switch process. In all other cases where IgG production was polyclonal, we have no indications for the induction of Ig switch. The fact that the more mature B-cell malignancies were T-cell-dependent for their differentiation might be a reflection of the in-vivo situation. The efficient induction of malignant B-cell differentiation described in this paper allows investigation of the antigen specificity of these antibodies.
Leukemia 1993 Oct
PMID:Differentiation of purified malignant B cells induced by PMA or by activated normal T cells. 810 56


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