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PubMed1989

Analysis of site of action of a choriocarcinoma-derived immunoregulatory factor on IL-2-mediated T cell responses.

We have investigated the functional ability of a choriocarcinoma-cell-derived factor to block human T cell responses and the factor's immunoregulatory site of action on the T cell signal transduction pathway. The factor completely suppressed human T cell responses activated by phorbol ester and calcium ionophore, reagents which strongly stimulate IL-2-mediated T cell responses. It failed to inhibit CD 25 expression and IL-2 production by T cell blasts in the T cell activation phase, but completely blocked recombinant IL-2-induced proliferation of T cell blasts in the T cell proliferation phase. Absorption experiments with the factor and Con A-induced T cell blasts as well as [125I]IL-2 binding experiments with T cell blasts revealed that the factor acted on the physiological events occurring after IL-2-mediated stimulation of IL-2 receptor complexes, demonstrating no interaction of the factor with either IL-2 molecules or IL-2 receptor complexes. Moreover, it suppressed murine IL-2 dependent T cell line proliferation, suggesting the presence of common pathways in human and murine T cell proliferation. The biological and immunological significance of the factor during pregnancy and in the immunosuppressed tumor-bearing hosts are discussed.

Calcimycin↗
PubMed1985

Hypercalcaemia in the accelerated phase of chronic myelogenous leukaemia: no relationship to the phenotype of the blast cells.

2 patients with chronic myelogenous leukaemia developed hypercalcaemia and severe myelofibrosis in the terminal phases of their disease. Hormonal studies excluded the hypercalcaemia being caused by primary hyperparathyroidism or ectopic parathyroid hormone secretion. Its development was unrelated to the phenotype of the blast cells, as assessed by conventional cytochemistry and immunological surface typing. The finding of increased urinary cAMP excretion in 1 of the patients suggests a circulating, nonparathyroid humoral bone resorbing factor with partial biological PTH-activity to be one of the pathogenetic mechanisms responsible for the occurrence of hypercalcaemia in patients with chronic myelogenous leukaemia.

Adult↗
PubMed1989

Kinetics of indium-111 chloride in chronic myelogenous leukaemia.

Indium-111 (111In) bound to transferrin incorporates transferrin receptors which emerge onto the cell membrane of leukaemic cells that have entered into the proliferative status. This study was undertaken to evaluate the kinetics of 111In chloride by counting blood cell radioactivity in five cases of chronic myelogenous leukaemia (CML). Leucocyte radioactivities reached a peak on the third to ninth day after 111In injection. In one case of mild leucocytosis in the early stage of the chronic phase, leucocyte activity was less than 14% of whole blood cell activity throughout the 14 day period. In two cases in the progressive stage of the chronic phase, and in two cases of blast crisis, 44 to 98% of whole blood cell activity at 48 h after 111In injection was occupied by the leucocyte fraction. Platelet radioactivities revealed maximum counts of only 0.1 to 0.4% of the injected dose on the sixth to tenth day. Accordingly, conventional marrow scintigraphy 48 h after 111In chloride injection seems to depict distribution of myelopoiesis rather than erythropoiesis in the progressive stage of the chronic phase and blast crisis in CML in addition to phagocytosis of 111In colloid by reticuloendothelial system.

Adolescent↗
PubMed1980

Relationship between the pretreatment proliferative activity of marrow blast cells and prognosis of acute lymphoblastic leukaemia of childhood.

Pretreatment marrow blast cells were studied in 38 boys and 27 girls (aged 1-14) with acute lymphoblastic leukaemia by flow cytometry after staining with propidium iodide.The percentage of blast cells in the S phase of the cell cycle ranged from 1% to 40% (median 6%). A correlation was found between the percentage of cells in S and the morphological classification of the French American British Cooperative Group (FAB), presence of T or B cell markers, haemoglobin concentration, blast size, bone pain, platelet count, and an inverse correlation with coarse granule and block staining with Periodic-acid-Schiff (PAS).63 of the 65 children attained complete remission. During the first 24 months of follow up there were fewer relapses (P = 0·054), and deaths (P = 0·004) in those children with 6% or fewer blasts in S phase. The difference was most marked in the first 12 months with 4 relapses out of 33 in the group with 6% or fewer cells in S compared with 13/30 in the group with > 6% cells in S.In order to investigate the prognostic significance of the pretreatment proliferative studies in greater detail, remission duration was correlated with 17 presenting features. Each feature was correlated individually and then the simultaneous effect of all the features was assessed by stepwise multiple regression.Only 3 features of the disease at diagnosis were individually correlated with duration of remission. These were% cells in S (P < 0·001), log white cell blood count (WBC) (P < 0·01) and the presence of T- or B-cell surface markers (P < 0·05). However, the multiple regression analysis showed that cell markers were not an independent prognostic feature, whereas the percentage cells in S and log WBC were independently and significantly correlated with duration of first remission (P < 0·001 in each case).

Acute Disease↗
PubMed1985

Cytogenetics and cell surface marker analysis in CML--1. Prediction of phenotype of acute phase transformation.

Thirty-nine patients with Philadelphia chromosome-positive (Ph1) chronic myelocytic leukemia (CML) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. Most of these abnormal populations had either an HLA.DR+ or an OKM1+ HLA.DR- phenotype. Thirteen patients progressed to acute phase disease. Five patients with HLA-DR+ abnormal cells during chronic phase showed no clonal evolution detectable using standard cytogenetic techniques and underwent lymphoid transformation. Seven patients with OKM1+-HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase. One patient with HLA.DR+ OKM1+ 63D3+ abnormal cells in chronic phase showed clonal evolution and progressed to a myelomonocytic acute phase. These results suggest that cell surface markers on chronic phase cells can be used in conjunction with cytogenetic monitoring to predict the phenotype of cells involved in the acute transformation of CML. B cells (6, 13), but not T cells (18), bearing the Ph1 have been isolated from chronic phase CML patients. Thus cells other than those of myeloid lineage may be involved. Periodic cytogenetic monitoring has been shown to detect clonal evolution (i.e. genetic changes in addition to the PH1) in as many as 75% of patients prior to the acute phase (14, 37). However, neither cytogenetic changes nor morphologic analysis appear to predict the lymphoblastic type of transformation (14). Since fluorescence analysis of cell surface markers has shown reduced numbers of normal cells (28), the identity of the 'abnormal' cells was probed with antibodies recognizing a variety of markers on immature and mature lymphoid and myeloid cells. Not only were significant numbers of abnormal cells detected in the peripheral blood of chronic phase patients, but the phenotype of the abnormal population, in combination with cytogenetic analyses, predicted the type of blasts involved in acute phase disease.

Adult↗
PubMed1985

Treatment of chronic myeloid leukemia blast crisis with vindesine and prednisone.

Sixteen patients in chronic myeloid leukemia blast crisis entered a phase II trial with vindesine and prednisone. Median duration of the chronic phase was 29 months in 13 patients, one previously had polycythemia vera, and two presented with a primary blast crisis. Eleven patients had myeloblastic features, as evidenced by morphology, cytochemistry, and cell surface antigens; three had a mixture of myeloid and lymphoid blast cells with lymphoblastic predominance; one had blast cells which displayed lymphoid characteristics; and one was classified as undifferentiated. Three patients had complete remissions lasting 1 month (myeloid), 3 months (mixed), and 5 months (lymphoid). Eleven patients had minor responses, with a median duration of 3 weeks (eight with myeloid, two with mixed, and one with undifferentiated). Two patients did not respond to vindesine. Leukopenia and thrombocytopenia were severe and prolonged independent of their morphologic or immunologic phenotype.

Adult↗
PubMed1995

Involvement of natural killer cells in chronic myeloid leukemia.

We assessed the involvement of natural killer (NK) cells in chronic myeloid leukemia (CML). We adopted the MAC (morphology antibody chromosomes) method, which allows simultaneous assessment of cell morphology, immunophenotype, and chromosome aberrations in the same mitotic or interphase cells. We examined three patients with CML in chronic phase and two patients with the disease in blast crisis. Patients in the chronic phase of the disease showed no involvement of NK cells, but involvement was detected in one of the patients in blast crisis. In this patient, a proportion of the B cells and lymphoid stem cells was also neoplastic, whereas mature postthymic T cells were normal.

Adult↗
PubMed1983

Lymphocyte blast transformation responses to mitogens and specific antigens in different clinical phases of multiple sclerosis: a follow-up study.

28 MS patients were studied at least 5 times for lymphocyte blast transformation responses to several mitogens (PHA, Con, PWM) and specific antigens (PPD, herpes simplex, measles, mumps, rubella), the mean duration of the follow-up being 15.3 months. Comparison of responses during remissions, exacerbations and ACTH treatment revealed no straight-forward association between the strength of response and clinical disease activity. Mitogen responses did not differ among various disease phases, but the PPD response was significantly lower during exacerbations than during remissions and still lower during ACTH treatment (P less than 0.05, Wilcoxon paired test). In responses to viral antigens, there was the same trend as in the PPD response. However, there were great individual differences in the behaviour of all antigen and mitogen induced lymphocyte responses. As a group, MS patients also showed more changes in their PHA mitogen responses during the follow-up than 8 control subjects followed similarly (P less than 0.005, F-test). The variation coefficient of the PHA response was also correlated with the maximal difference in the Fog neurologic deficit scale during the follow-up time (r = 0.460, P less than 0.05). However, patients with greatest clinical changes most often also received ACTH treatment, which may affect the results. The follow-up results of individual patients revealed that some had quite regular patterns of decreasing responses during disease relapses, whereas others had more irregular wide fluctuations of responses.

Adrenocorticotropic Hormone↗
PubMed1986

A neutrophil membrane marker reveals two groups of chronic myelogenous leukemia and its absence may be a marker of disease progression.

An IgG1 monoclonal antibody, 31D8, that recognizes normal neutrophil (PMN) membranes, was used to study PMN from patients with chronic myelogenous leukemia (CML). Nineteen patients with Philadelphia chromosome positive CML were followed over a ten-month period and compared with 23 normals, six patients with leukemoid reactions, and eight patients with phagocytic cell defects. The percentage of PMN binding of 31D8 among normal subjects was variable about a normal distribution with an average of 95 +/- 2% of cells binding 31D8. In contrast, there were two groups of CML patients: in 14 patients 88 +/- 3% PMN bound 31D8 while in the remaining five patients only 6 +/- 6% PMN bound 31D8. PMN 31D8 binding was normal in the control patient groups. Control antibodies 7C3 (binds to PMN precursors) and OKM1 (binds to the CR3 (iC3b) receptor) bound normally to CML neutrophils. Functionally, CML cells had normal chemotaxis to several stimuli and normal superoxide generation to phorbol myristate acetate. However, superoxide production in response to fmet-leu-phe was significantly less in 31D8 negative CML PMN than both 31D8 positive CML PMN and normal PMN which contained 85% 31D8 positive and 15% 31D8 negative PMN. Clinically, 2 of 14 CML patients with 31D8 positive PMN were in blast crisis (one extramedullary) at the time of study and the other 12 patients remained clinically stable in the chronic phase during the ten months of study. In contrast, one of five patients with 31D8 negative PMN was in blast crisis at the time of study and all four of the remaining patients progressed to either the accelerated phase or blast crisis. Three of these patients died of their disease eight to ten months after their initial study. Thus, failure of CML cells to bind 31D8 may be useful for predicting which patients are likely to progress to the accelerated phase or blast crisis.

Antibodies, Monoclonal↗
PubMed1993

Recombinant human granulocyte colony-stimulating factor in combination with continuous infusion of cytosine arabinoside for the treatment of refractory acute myelogenous leukemia.

Because recombinant human granulocyte colony-stimulating factor (G-CSF) has been reported to increase the sensitivity of acute myelogenous leukemia (AML) blast cells to cytosine arabinoside (Ara-C) in vitro, we treated a patient with refractory AML with an Ara-C-based regimen in combination with G-CSF (G-CSF/Ara-C therapy). G-CSF (50 micrograms/m2/day, subcutaneous injection) was administered simultaneously with a continuous intravenous infusion of Ara-C (70 mg/m2/day). Complete remission was achieved, however, severe neutropenia, documented infection, stomatitis, and diarrhea were observed. In vitro studies using 3H-thymidine uptake and dual parameter flow-cytometric analysis of DNA and proliferating cell nuclear antigen showed that leukemic blast cells in S phase were increased after incubation with G-CSF. G-CSF also enhanced expression of the transferrin receptor (CD71) on blast cells in vitro. These observations suggest that G-CSF/Ara-C therapy may be useful in the treatment of high-risk AML.

Bone Marrow↗
PubMed1990

Effect of interleukin 3 on cytosine arabinoside-mediated cytotoxicity of leukemic myeloblasts.

The concept of biologic modification of proliferation and differentiation of myeloid leukemia cells has attracted much attention over the past years. One promising strategy involves the recruitment of leukemic cells into the cell cycle by hematopoietic growth factors in combination with cycle-specific cytotoxic drugs. Because cytosine arabinoside (Ara-C), which targets only cells in S-phase of the mitotic cell cycle, is included in most chemotherapeutic regimens for the treatment of acute myelogenous leukemia, we explored the hypothesis that the recruitment of quiescent immature leukemic blasts into the cell cycle by the early acting growth factor interleukin 3 (IL-3) can increase the efficacy of Ara-C for kill of leukemic stem cells. We show that IL-3 increases the fraction of blasts in S-phase, as assessed by DNA histogram analysis with propidium iodide staining, leading to an enhancement of kill of clonogenic blast cells when combined with Ara-C. Expression of the protooncogenes c-myc, c-fms, and c-fos, known to be linked to cellular proliferation and differentiation, was also altered by IL-3 in Ara-C-treated cultures, further substantiating the role that IL-3 plays as an enhancer of the cytotoxicity of Ara-C.

Antigens, CD↗
PubMed1999

Lipid peroxidation in leukaemia.

OBJECTIVE: Free radicals have been implicated in the pathogenesis of leukaemias, so the degree of lipid peroxidation was studied as a marker of disease activity in patients of leukaemia. METHODS: Lipid peroxidation product malonyldialdehyde (MDA) was estimated in serum from 30 patients of leukaemia by thio-barbituric acid reaction before and after chemotherapy. There were 10 patients of acute myeloid leukaemia (AML), 5 with acute lymphocytic leukaemia (ALL), 15 with chronic myeloid leukaemia (CML) of which 10 were in chronic stable phase and 5 in blast crisis. Twenty healthy age and sex matched individuals served as control. RESULTS: There was a significant increase in MDA levels in AML and ALL patients and serum MDA levels were higher in the active phase of disease than in remission. We observed a direct correlation between peripheral leucocyte counts and MDA levels. In CML, MDA levels were higher, more so in the patients who were in blast crisis. Patients of CML blast crisis who achieved remission showed a significant decrease in MDA levels as compared to those without remission. CONCLUSION: We observed a significant increase in MDA levels in active phase of acute as well as chronic leukaemia than those in remission. The proposed mechanism for high MDA is that myeloid cells are a major source of superoxide and other oxygen metabolites which lead to lipid peroxidation. MDA estimation in leukaemia can be of help in detecting type of leukaemia, response of therapy, and to predict the chances of relapse.

Case-Control Studies↗
PubMed2001

Human T cell activation induces the expression of a novel CD45 isoform that is analogous to murine B220 and is associated with altered O-glycan synthesis and onset of apoptosis.

Activated T cells undergo changes during their transition to T cell blasts and, subsequently, via a phase of anergy, to apoptosis. For example, activated murine T cell blasts express the B-cell-specific CD45R isoform, B220, a marker also present on T cells in mice and humans with defective Fas-mediated apoptosis in vivo, suggesting a role for B220 up-regulation in the transition of activation to apoptosis. Human T cells, activated in vitro with superantigens and mitogens, also express B220 as they undergo blastogenesis and cell cycle progression. B220 expression peaks on T cells undergoing apoptosis. CD43-hexasaccharide glycoform expression and lectin binding profiles indicate that B220 expression is reflective of altered O-linked glycan biosynthesis found in specific T cell subsets transitioning through the phases of proliferation, anergy, and apoptosis. Potential implications of these alterations include changes in lymphocyte adhesion and trafficking and homeostasis through altered sensitivity to Fas-dependent and independent pathways of apoptosis.

Adult↗
PubMed1989

Chromosomal characteristics of Ph-positive chronic myelogenous leukemia in transformation. A study of 23 Chinese patients in Taiwan.

Cytogenetic study was performed in the past 3 years on 23 Chinese patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) in transformation; seven were in accelerated phase and 16 in acute blast crisis. Chromosomal abnormalities in addition to Ph were found in three (43%) of the patients at accelerated phase and 14 (88%) of the patients at blast crisis. The common nonrandom chromosomal aberrations were double Ph, trisomy 8, trisomy 19, and trisomy 21, which occurred in 47%, 41%, 35%, and 29%, respectively, of the total patients with extra chromosomal abnormalities. Isochromosome for the long arm of chromosome 17 was found in only one patient. In patients with blast crisis, the type of blast cell was characterized through morphologic, cytochemical, and immunocytochemical studies. Eleven cases were classified as myeloid and five as lymphoid transformation. Trisomy 8, 19, and 21 were detected only in patients with myeloid blast crisis. This study also revealed a high incidence of trisomy 21 and a low incidence of i(17q) in Chinese patients with transformation of CML.

Adult↗
PubMed1991

Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens.

Techniques which identify hapten-specific B cells in tissues have been used to determine the sites of B cell activation in rat spleens in response to T cell-dependent (TD) antigens and T cell-independent type-1 (TI-1) antigens. Surface-associated hapten binding by specific memory B cells and B blasts was distinguished from the strong cytoplasmic hapten binding by specific plasma cells and plasmablasts. Blast cells in S phase were identified in tissue sections by staining cells which had been pulse labeled in vivo with 5-bromo-2'-deoxyuridine. Hapten-specific B blast cells are found in three sites: (a) around interdigitating cells in the T cell-rich zones; (b) in the follicular dendritic cell network and (c) in association with macrophages in the red pulp. Hapten-binding memory B cells, which are not in cell cycle, accumulate in the marginal zones and to a lesser extent the follicular mantles in response to TD and TI-1 antigens. The hapten-specific blast response in T zones is confined to the first few days after antigen is given and is low for primary responses to TD antigens, but massive on secondary challenge, when marginal zone memory B cells migrate to the T zones. Both the primary and secondary T zone responses to TI-1 antigens are impressive and in these responses hapten-specific B blasts are also found in the splenic red pulp. The follicular response to TD antigens starts with a small number of B blasts (fewer than five) entering each follicle. These increase in number exponentially so that by the 4th day after immunization they fill the follicle. The oligoclonality of the response is shown in simultaneous responses to two haptens where 6%-31% of the follicles on day 3 after immunization contain blasts specific for only one of the two haptens. During the 4th day classical zonal pattern of germinal centers develops. The surface immunoglobulin-positive B blasts are lost from the follicle center, while one pole of the follicular dendritic cell network fills with surface immunoglobulin-negative centroblasts. Centroblasts do not increase in numbers but divide to give rise to centrocytes, which re-express sIg and migrate into the follicular dendritic cell network. Cell kinetic studies indicate that the centrocyte population is renewed from centroblasts every 7 h. Centrocytes either leave the germinal center within this time or die in situ.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1998

Expression of cell cycle regulatory genes in chronic myelogenous leukemia.

BACKGROUND AND OBJECTIVE: Cell cycle regulatory genes are frequently altered in a variety of malignancies. The structure and pattern of expression of eight genes involved in cell division cycle control were studied in leukemic cell samples prepared from bone marrow of patients affected by chronic myelogenous leukemia. DESIGN AND METHODS: Ten cell preparations were obtained from patients in the chronic phase, five from those in myeloid blast crisis and five from those in the lymphoid acute phase. Moreover, bone marrow CD34+ cells, purified from healthy subjects and patients with chronic myelogenous leukemia (both during chronic and acute phases), were analyzed. The investigated genes were RB1, p53 and six cyclin-dependent kinase inhibitor genes (p15INK4B, p16INK4A, p18INK4C, p21WAF1/CIP1, p27Kip1, p57Kip2). RESULTS: We found that none of these genes is structurally altered in either the chronic or acute phases, with the single exception of the p16INK4A gene, which was homozygously deleted in 1 case of lymphoid evolution. p57Kip2 expression is down-regulated during the evolution towards the blast crisis both in malignant and CD34+ cells. In addition, a significant up-regulation of p15INK4B gene expression is observable during the development of the acute phase of malignancy. INTERPRETATIONS AND CONCLUSIONS: The transcriptional modulation of some cyclin-dependent kinase inhibitors might contribute to the fatal blast crisis of chronic myelogenous leukemia.

Blast Crisis↗
PubMed2000

Acquired loss of p53 induces blastic transformation in p210(bcr/abl)-expressing hematopoietic cells: a transgenic study for blast crisis of human CML.

Chronic myelogenous leukemia (CML) begins with an indolent chronic phase but inevitably progresses to a fatal blast crisis. Although the Philadelphia chromosome, which generates p210(bcr/abl), is a unique chromosomal abnormality in the chronic phase, additional chromosomal abnormalities are frequently detected in the blast crisis, suggesting that superimposed genetic events are responsible for disease progression. To investigate whether loss of p53 plays a role in the evolution of CML, we crossmated p210(bcr/abl)-transgenic (BCR/ABL(tg/-)) mice with p53-heterozygous (p53(+/-)) mice and generated p210(bcr/abl)-transgenic, p53-heterozygous (BCR/ABL(tg/-)p53(+/-)) mice, in which a somatic alteration in the residual normal p53 allele directly abrogates p53 function. The BCR/ABL(tg/-)p53(+/-) mice died in a short period compared with their wild-type (BCR/ABL(-/-)p53(+/+)), p53 heterozygous (BCR/ABL(-/-)p53(+/-)), and p210(bcr/abl) transgenic (BCR/ABL(tg/-)p53(+/+)) litter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembling human CML. The blast cells were clonal in origin and expressed p210(bcr/abl) with an increased kinase activity. Interestingly, the residual normal p53 allele was frequently and preferentially lost in the tumor tissues, implying that a certain mechanism facilitating the loss of p53 allele exists in p210(bcr/abl)-expressing hematopoietic cells. Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p210(bcr/abl)-expressing hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML. (Blood. 2000;95:1144-1150)

Animals↗
PubMed1999

Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte-colony stimulating factor.

Twenty-one patients with advanced chronic myeloid leukemia (late chronic phase (n = 8), accelerated phase (n = 11) and blast crisis (n = 2)) were treated with idarubicin, cytarabine, and etoposide followed by G-CSF and subsequent collection of peripheral blood progenitor cells in the early recovery phase. Treatment was reasonably well tolerated with no deaths or intensive care admissions. Despite the advanced phase of disease and heavy pretreatment with cytotoxics and interferon-alfa, 11 of 21 patients (52%) achieved a cytogenetic response. Of the nine major cytogenetic responses (complete (n = 3) and partial (n = 6)), seven achieved adequate progenitor collections for consideration for autologous transplantation. The only predictor of response was disease duration (P = 0.02). With a median follow-up of 1171 days from treatment it appears unlikely that G-CSF contributed to disease progression. Survival post-IcE was predicted by disease stage (P = 0.0001). Intensive chemotherapy followed by G-CSF allowed adequate yields of predominantly Philadelphia chromosome negative progenitor cells to be obtained from one-third of patients with advanced CML.

Adult↗