Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a patient who at the time of kidney transplantation for polycystic kidney disease was found to have an enlarged inguinal lymph node which later demonstrated evidence of extra medullary granulopoiesis. During the first two weeks following kidney transplantation, a striking leukemoid pattern developed and 2 months after transplant the patient was diagnosed with acute myelogenous leukemia (AML). Retrospective analysis of peripheral blood cytokines over this time revealed elevated levels of GMCSF and gamma IFN at the time of peak peripheral blood WBC with subsequent peaks in IL-4, IL-6 and IL-2 as the peripheral blood WBC fell. A rise in levels of TNF alpha also preceded the peripheral blood WBC rise (although these concentrations were at or below those following uncomplicated kidney transplants). The clinical course of AML in this patient was marked by relentless relapse despite chemotherapy. The possibility of cytokine facilitated tumor growth is discussed.
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PMID:Early development of acute myelogenous leukemia following kidney transplantation: possible role of multiple serum cytokines. 857 65

Expression of the interleukin-2 receptor alpha-(IL-2Ralpha-), IL-2Rbeta-, and the recently identified IL-2Rgamma-chain was examined on a wide range of cells of myeloid origin including neutrophils, monocytes, normal bone marrow-derived myeloid progenitors enriched for CD34+ cells, bone marrow blasts obtained from acute myelogenous leukemia (AML) patients, and permanent myeloid leukemia cell lines by reverse transcriptase-polymerase chain reaction and surface membrane analysis using receptor chain-specific monoclonal antibodies and flow cytometry. Expression of the p75 IL-2Rbeta- and the p64 IL-2Rgamma-chain was a common finding in most of the myeloid cell samples investigated, whereas IL-2Ralpha-chain was less frequently expressed. Although the high-affinity IL-2R form (ie, the alpha+, beta+, gamma+ IL-2R form) was detectable in a small minority of primary AML samples as well as the KG-1 cell line and IL-2 binding to these cells was sufficient to initiate signal transduction as evidenced by an increase in overall protein tyrosine phosphorylation and more specifically in tyrosine phosphorylation of the Janus kinase (JAK) 3, in none of these cell types did exposure to IL-2 affect cell growth kinetics. These results suggest that, in myeloid cells, the IL-2R may not stimulate mitogenic responses or that its components may be expressed in a combinational association with receptors for other cytokines and that IL-2Rgamma may play a regulatory role in normal and malignant myelopoiesis possibly independent from IL-2. Because recent studies by others have indicated that the IL-2Rgamma- chain may be shared by the IL-4R, the IL-7R, and most likely the IL-9R, expression of mRNA of these receptor types was also investigated in these cell samples. Surprisingly, in a substantial part of the myeloid lineage cells examined, an IL-2Rgamma+, IL-4R-, IL7R- configuration was noted that was, however, frequently associated with expression of IL-9R. Sharing of IL-9R/IL-2R components was furthermore suggested by inhibition of 125I-IL-2 binding to primary AML cells with excess of unlabeled IL-9.
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PMID:Transcript synthesis and surface expression of the interleukin-2 receptor (alpha-, beta-, and gamma-chain) by normal and malignant myeloid cells. 863 Apr 6

A ligand for the flt3 tyrosine kinase receptor (flt3R) has recently been cloned. Forty-three cases of childhood acute myeloid leukemia (AML) and 27 cases of childhood acute lymphocytic leukemia (ALL) were examined by flow cytometric analysis for cell-surface flt3R and proliferative response in vitro to flt3 ligand (flt3L). Flt3R was commonly expressed on the cell surface of leukemic cells from all AML subclasses and B-ALL, but we did not detect cell-surface flt3R on T-ALL. Flt3L alone induced the proliferation of the monocytic AML-M5 cells and some erythroleukemic AML-M6 cells. Some isolated instances of weak proliferative responses were also noted in other AML subclasses. Interleukin-4 (IL-4) alone inhibited the proliferation of a group of AML-M5 cells and, when combined with flt3L, suppressed the proliferative effect of flt3L. In general, B-ALL and T-ALL cells failed to respond to flt3L alone or in the presence of combinations of IL-2, IL-3, or IL-7.
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PMID:Effects of flt3 ligand on acute myeloid and lymphocytic leukemic blast cells from children. 864 69

We report our observations with the cell line LW/SO, which was recently derived from the bone marrow of a patient with acute myeloid leukemia. Based on the morphological and histochemical examination, the leukemic cells were classified primarily as FAB type M4. However, 2 years later, in relapse, the cells changed their morphology and were hence specified as FAB type M2 (slightly positive for acid phosphatase and Sudan black). The cells established have now been in culture for approximately 11 months and display nearly 100% CD4/5/7/15/25/71/120a,b at varying densities. Some of them spontaneously and reversibly become either CD34 + /38- or CD34 - /38+, yet the majority of the cells remain negative for both. All attempts to separate the cells with a distinct phenotype by limiting dilution or sorting through a flow cytometer failed repeatedly. The subsets, enriched up to 98% (regardless of their primary immunophenotype CD34 - / 38-, CD34 + /38-, or CD34 - /38+), soon displayed a phenotypical constellation similar to that before sorting. The ratio of CD34- to CD34+ seems to be influenced by the cell density: The greater the cell-to-cell contact, the lower the percentage of CD34-expressing cells. Some of the cells apparently differentiate into T-cell phenotype and acquire CD3 and T-cell receptor (TCR) alpha/beta molecules. While the quantity of CD34-expressing cells significantly increased in the presence of dexamethasone (10(-7) M), and some of them additionally acquired CD33 antigen, the percentage of CD3-positive cells was enhanced by adding 1% DMSO in medium. In contrast, cytokines such as IL-1, IL-2, IL-3, IL-4, IL-6, G-CSF, GM-CSF, or SCF (c-kit ligand) altered neither the proliferation capacity nor the phenotypical constellation of LW/SO cells (each tested alone). Although normal karyotype was obtained from the bone marrow cells, the LW/SO cells revealed a homogeneous chromosomal composition of 45, X, -X, der(9) inv(9) (p12q13) del(9) (p22?). These data suggested that LW/SO cells might be the leukemic counterpart of putative pre-CD34-positive progenitors. In order to substantiate this assumption, we analyzed the expression of other so-called T-cell markers on CD34+ cells from peripheral blood stem cell aphereses of five patients who later underwent high-dose chemotherapy and subsequent stem cell retransfusion. These data clearly revealed that a considerable amount of CD34+ hematopoietic progenitors co-express CD2/4/(5)/(7)/25 at an early stage of differentiation, and support the notion that CD34-negative LW/SO cells with the surface markers CD4/5/7/25 are probably phenotypical representatives of pluripotent stem cell. Hence, not all CD34-negative populations with so-called T-cell surface markers should be considered T-cells; some may constitute the ancestor of CD34 antigen-expressing progenitors.
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PMID:LW/SO cell line: a tool for studying the phenotypical characterization and commitment of hematopoietic stem cells. 864 43

The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of 'induction' IL-2 of 9, 10, or 12 x 10(6) IU/m2/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 x 10(6) IU/m2/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 x 10(6) IU/m2/day x 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.
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PMID:Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study. 905 8

We established a factor-independent acute myeloid leukemia cell line, designated Ei501. The line has been growing in RPMI 1640 media for 18 months and can be maintained without addition of growth factors. Ei501 is positive for myeloperoxidase and negative for esterase and PAS. Cytogenetic analysis revealed the FAB M3 associated t(15;17) translocation and a translocation of the chromosomes 7 and 8: 46 XX, -7, +t(7;8)(q32;q13), t(15;17)(q22;q12). This karyotype was confirmed by fluorescence in situ hybridization. Ei501 cells express AML-associated surface markers such as CD13, CD33 and CD38. Although 42% of the patient's blast cells were CD34-positive, the line lacks surface expression of CD34. Furthermore the line has a number of characteristics which are detectable in blasts from AML patients, such as surface adhesion molecules, cytokines such as TGF-beta, cytokine receptors such as the IL-2 receptor beta and gamma chains or the IL-4 receptor and the genes for the transcription factor wt-1 (Wilms' tumor gene) and for the proto-oncogene bcl-2, both shown to be present in the majority of patients with AML. Additionally the line can be used as target in cytotoxicity assays using IL-2 activated cytotoxic lymphocytes as effector cells. In conclusion, besides a rare karyotype the Ei501 cell line has several features common in AML, and may therefore be used as a model to study pathogenetic mechanisms in acute myeloid leukemia.
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PMID:Establishment and characterization of a new, factor-independent acute myeloid leukemia line designated Ei501. 918 Feb 96

lnterleukin-2 (IL-2) is known to cause xerostomia and skin manifestations similar to graft-versus-host disease (GVHD). We therefore evaluated major salivary gland function in patients with hematological malignancies treated with IL-2 and interferon-alpha (IFN-alpha) after ABSCT. Eleven patients (seven male, four female) of median age 40 (24-47) were evaluated, seven with non-Hodgkin lymphoma (NHL); one with Hodgkin's disease (HD) and three with acute myelogenous leukemia (AML). Parotid and submandibular salivary gland function was assessed before, during and after IL-2/IFN-alpha administration by evaluation of the salivary flow rate and the composition of secreted saliva. Significant reductions in both the resting and stimulated parotid and submandibular salivary flow rates were observed during IL-2/IFN-alpha immunotherapy compared with the pre- and post-therapy values (P < 0.01), while no hyposalivation was observed in the control patients who underwent ABSCT and did not received IL-2. Sialochemical evaluation revealed a significant increase in potassium concentration (24.4+/-0.6 mEq/l to 28.9+/-1.4 mEq/l) and a significant decrease in sodium concentration (6.7+/-2.1 mEq/l to 3.3+/-1.0 mEq/l) (P < 0.05) in the stimulated parotid gland saliva secreted during IL-2/IFN-alpha administration. Salivary protein concentrations were not altered by the IL-2/IFN-alpha immunotherapy. Similar changes were previously observed in mice and humans with chronic GVHD. We conclude that IL-2 immunotherapy induces major salivary gland dysfunction in humans, similar to our previous observations in patients with chronic GVHD, which may indicate similar pathophysiologic mechanisms.
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PMID:Major salivary gland dysfunction in patients with hematological malignancies receiving interleukin-2-based immunotherapy post-autologous blood stem cell transplantation (ABSCT). 933 59

Cytotoxic effector cells are generated when autologous hematopoietic cells (HSC) are cultured with IL-2 for 24 h. Infusion of these cells followed by IL-2 administration may moderate a graft-versus tumor (GvT) effect in vivo. Sixteen patients--7 with non-Hodgkin's lymphoma (NHL), 2 with AML, 4 with multiple myeloma (MM), and 3 with Hodgkin's disease (HD)--received busulfan (4 mg/kg/day for 4 days) and cyclophosphamide (60 mg/kg/day for 2 days) or cyclophosphamide/TBI (1320 cGy). Autologous HSC were activated by culturing with IL-2 for 24 h before reinfusion. Subcutaneous administration of IL-2 began after engraftment at 1.8 x 10(6) IU/m2/day for 1-4 weeks. Neutrophil engraftment occurred on day 13.1 (median) (range 9-45 days), and platelet engraftment occurred on day 19.3 (median) (range 7-54 days) for 15 patients, with delayed engraftment observed in 3 patients. One patient experienced a fatal cardiac arrhythmia. Five patients developed transient skin rashes with histologic evaluation demonstrating findings consistent with GvHD. At 17 months (median) (range 7-23 months), 9 patients are alive, with 6 patients remaining disease free. This pilot trial demonstrates mild to moderate toxicities and a possible delay in platelet engraftment. Further trials will determine the optimal dose and duration of IL-2 therapy and possible impact of this therapy on survival. Laboratory investigations are evaluating the presence of autologous GvHD and a possible GvT effect.
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PMID:A pilot study evaluating interleukin-2-activated hematopoietic stem cell transplantation for hematologic malignancies. 936 82

Clinical data and animal models afford evidence for anti-leukemia immunity in humans, but the interactions critical for blast cell recognition are unresolved. Expression of B7 molecules by antigen-presenting cells (APC) provides co-stimulatory signals to T lymphocytes via CD28 and CTLA-4 which prevent the induction of alloantigen-specific tolerance. Conversely, expression of CD40 ligand by stimulated T cells activates APC via CD40. In human hematological B cell malignancies (follicular lymphoma and chronic lymphocytic leukemia), the defect in alloantigen presentation of tumoral cells can be repaired by up-regulation of B7 and other co-stimulatory molecules via CD40. We studied the role of B7 molecules in alloimmune recognition and the various ways to improve the antitumoral response on peripheral blood leukemic cells from 20 patients with a diagnosis of primary acute myeloid leukemia (AML). We focused on myelo/monocytic M4/M5 French-American-British classification subtypes which are considered as the neoplastic counterpart of normal monocytes, a prototypic APC. In one-way mixed lymphocyte reaction of CD4+ T cells against leukemic cells, differences in B7-1, B7-2 or CD40 expression by AML cells did not induce specific cytokine secretion; interleukin (IL)-2 and interferon (IFN)-gamma were detected but not IL-4, corresponding to a Th1 pattern. Blockade experiments showed that proliferation and IFN-gamma secretion only partially depended on B7 molecules, which in contrast had a pivotal role in IL-2 synthesis. In contrast with murine models which suggest a pivotal role for CD80/B7-1 in the immune response against AML, our data support a greater role for CD86/B7-2, in line with the baseline expression of CD86/B7-2 and lack of CD80/B7-1 on most M4/M5 AML cells. AML cell stimulation via CD40: (1) significantly improved IL-2 secretion but not proliferation of responding T lymphocytes, (2) increased CD54/ICAM-1 expression in three quarters of cases, (3) failed in most cases to induce CD40-specific CD80/B7-1 up-regulation, and (4) had a weak effect on CD86/B7-2 expression. These data contrast with the very efficient up-regulation of both B7 co-stimulatory molecule expression and tumoral cell alloimmune recognition following CD40 stimulation in B cell malignancy models. The role of the defective B7 molecule up-regulation by the CD40 pathway in inefficient tumor immunogenicity of primary AML cells has to be further investigated, in particular using transfection experiments of CD80/B7-1-deficient AML cell lines. From our in vitro data we conclude that B7 molecules play an important role in the alloimmune surveillance of AML as suggested by the high B7 molecule dependency of IL-2 secretion. Nonetheless, the contribution of B7 molecules to alloimmune T cell proliferation against primary AML cells in human and the way to improve it--regulation via CD40 in particular--differ from B cell malignancies and murine models, suggesting the requirement for specific strategies in the development of antitumor immunity.
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PMID:Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition. 948 89

We have investigated the susceptibility of primary acute myeloid leukaemia (AML) samples to the lytic action of normal peripheral blood mononuclear cells (PBMC), as well as of the patients' autologous and allogeneic PBMC collected at the time of remission following stimulation with different concentrations of interleukin (IL)-2 and IL-12, both alone and in variable combinations. Primary AML blasts were resistant to IL-2-activated PBMC effectors generated from normal individuals, allogeneic and autologous patients in five, six and eight of the 10 AML samples tested, respectively, IL-12 alone proved ineffective in generating anti-leukaemic activity, whereas, in combination, the two cytokines induced anti-leukaemic killing in all five cases resistant to normal PBMC, in 4/6 samples resistant to allogeneic AML effectors and in 5/8 cases resistant to autologous effectors. In each case the lytic effect was maintained at the lowest cytokine combination (10 + 10 IU/ml) utilized. The suggestion of a synergistic effect was further strengthened by the evidence that at the lowest doses of IL-2 and IL-12 the degree of killing was greater than that promoted by each cytokine independently. The results of this study suggest that two major limitations associated with the administration of IL-2 to AML patients, the resistance of the blasts to IL-2-generated killing and the toxicity associated with high-dose IL-2, may be overcome by the combined use of very low doses of IL-2 and IL-12. As IL-2-resistant blasts may be lysed by a low-dose combination of IL-2/IL-12, feasibility studies with this cytokine combination are worthy of exploration in vivo.
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PMID:Cytotoxic effectors activated by low-dose IL-2 plus IL-12 lyse IL-2-resistant autologous acute myeloid leukaemia blasts. 957 95


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