Mechanisms of glucocorticosteroid activity in patients with the preleukemic syndrome (hemopoietic dysplasia).
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Cells, Cultured↗
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Chromosomes and prognosis in preleukaemia: four cases of 5q-- with other karyotypic abnormality.
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Adult↗
Distribution of preleukemic cells in fractionated bone marrow of mice.
Separation of preleukemic cells (having the potential to develop further into overt T-cell leukemias) from bone marrow cell populations was attempted. Donor mice of preleukemic bone marrow included C57BL/6 mice inoculated intrathymically with D-RadLV or AKR/J mice carrying spontaneous preleukemic cells among their bone marrow cells. Fractionation of bone marrow cells suspended in bovine serum albumin (BSA) by equilibrium density centrifugation or by velocity sedimentation at 1 g unit gravity using discontinuous density gradient of Ficoll was applied. The leukemogenic potential of the separated bone marrow fractions was tested by evaluating leukemia development following their transfer into appropriate recipients. No enrichment of D-RadLV-induced preleukemic cells was found in any of the four bone marrow fractions obtained following separation on BSA gradient. Separation of D-RadLV-induced preleukemic cells was afforded by using the Ficoll gradients. Preleukemic cells were located mainly among four out of 21 fractions tested, consisting mostly of 10 to 14 micrometers size cells. In contrast, preleukemic cells from AKR donors were distributed among most of the separated fractions. It is suggested that these variable results may reflect homogeneity or heterogeneity of progenitor target cells undergoing transformation.
Animals↗
The prognostic value of chromosome studies in patients with the preleukemic syndrome (hemopoietic dysplasia).
Banded chromosome studies obtained at the time of diagnosis from 42 patients with the preleukemic syndrome had clonal abnormalities in fifteen. Using Kaplan-Meier product limit survival analysis, it was found that patients with chromosome abnormalities developed acute leukemia more frequently than those without (p less than 0.05). However, we noted that in a subset of patients with complex abnormalities and in a subset previously exposed to alkylating agents, almost all developed leukemia. When either subset was excluded from the larger group analysis there were no differences in leukemia-free survival between cytogenetically abnormal and normal groups. Thus, in the prognostic evaluation of our patients with the preleukemic syndrome a chromosome abnormality per se did not predict rapid evolution to acute leukemia. However, almost all preleukemic patients with complex chromosome abnormalities and almost all alkylator-exposed preleukemic patients can be expected to develop overt leukemia within 1 yr.
Alkylating Agents↗
Prognostic value of the combined suicide level of granulocyte progenitors and the labelling index of precursors in preleukemic states and oligoblastic leukemias.
Although abnormalities in granulopoiesis detected by means of bone marrow cytology, culture and kinetic studies have provided prognostic data in preleukemic states and oligoblastic leukemias, this information cannot be applied to individual cases. In order to determine the indications for treatment and the form it should take in a given case, data would be required concerning the probability of impending transformation into acute leukemia. In 45 studies involving 34 patients who were followed for 10-42 months, a combination of a rise in the proportion of granulocyte precursors in S-phase, indicated by a colony-forming cell suicide rate of over 40%, and a low labelling index of myeloblasts and promyelocytes, was always followed by the onset of acute leukemia within 10 months. Sequential studies in 13 patients revealed an increase in cluster-forming cells and in the suicide level in the second study. The changed kinetics of granulopoietic proliferation may provide an indication for chemotherapy.
Cell Division↗
Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia.
Several agents, including arabinosyl cytosine (ARA-C) at a low concentration, can induce leukemic myeloblasts to mature to a variable extent. The therapeutic implications of this observation are worth investigating. A few case-reports have shown that low dose ARA-C can be useful for treatment of the myelodysplastic syndromes (MDS) and of acute myeloid leukemia (AML). However, no information is available yet on the proportion of patients who can be expected to respond. We treated by low dose ARA-C (20-30 mg/sqm/day i.v. or i.m. for 7-10 days) 20 consecutive patients. A complete remission of 5 months was obtained in one of nine cases of subacute myeloid leukemia (SAML). A partial remission (complete normalization of blood counts with a slight excess of marrow blast cells) was obtained twice in one of 11 cases of MDS. An increase of Hb level (more than 11.5 g/dl) was obtained and maintained for 12 months in a case of MDS. A short-lasting increase of granulocyte count was obtained in another two cases of MDS and SAML respectively. It is suggested that low dose ARA-C can advantageously modify the proliferation to maturation imbalance of leukemic cells by slowing down cell proliferation rate. However, the proportion of patients who respond is probably low. This treatment is at a very early experimental stage and should be probably limited to selected cases of MDS and subacute or acute myeloid leukemia.
Adult↗
Thymic nurse cells account for the thymus dependency of preleukemic cells in mice after inoculation of radiation leukemia virus.
Inoculation of Radiation Leukemia Virus (RadLV) into C57BL/Ka mice induces thymic lymphomas after a 3-6 month latent period. The leukemogenic process requires a sequence of events from the productive infection of susceptible target cells and induction of preleukemic cells to irreversible neoplastic transformation. Preleukemic cells were detected in the thymus during the first week following virus injection. The thymus dependency of these cells was shown to depend transiently upon peculiar lymphoepithelial complexes called "Thymic Nurse Cells" (TNCs). Indeed, the first preleukemic cells appearing in the RadLV-inoculated thymuses were observed selectively within TNCs. They remained closely associated with these complexes during the first 2 or 4 weeks. Later on, TNCs disappeared almost completely whereas non-TNCs associated preleukemic cells were found. Lymphoepithelial interactions within TNCs were thus required for the initial events of RadLV-induced lymphomagenesis. The subsequent TNCs depletion expressed a disturbance of thymic lymphopoiesis in relation with the neoplastic process.
Animals↗
Platelet DNA polymerase levels in CML: implications for oncogenesis.
Partially purified platelet DNA polymerase (PDP) was able to synthesize DNA transcripts of platelet polyadenylated RNA. PDP was elevated in the earliest stages of CML and PV. In PV, successful chemotherapy resulted in rapid return of PDP to normal levels while in CML this was not the case. An hypothesis is presented proposing that PDP contributes to oncogenesis by regulating the expression of oncogenes.
Blood Platelets↗
Natural killer (NK)-cell activity and antibody-dependent cellular cytotoxicity (ADCC) in primary preleukemic syndrome.
In 13 patients with a multi-parameter based diagnosis of primary acquired preleukemic syndrome (PPS), natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) were investigated on peripheral blood mononuclear cell (MNC) fractions. In all but two patients a defective NK activity was found. Lymphocyte-monocyte mixture experiments demonstrated that this was not due to suppressor monocytes. Furthermore, NK activity was defective when both myeloid and non-myeloid target cell lines were used. Addition of human leukocyte interferon to the NK cultures augmented the cytotoxicity, which exhibited the same kinetics as that of normal controls, but NK activity levels remained subnormal. These data strongly indicate that the decreased NK activity seen in the patients is due to a decreased number of circulating NK cells. In contrast ADCC was within the normal range both when MNC suspensions as well as when purified peripheral blood lymphocytes were used as effector cells thus ruling out subnormal lymphocyte ADCC masked by the presence of monocyte ADCC. These results demonstrate that PPS patients have a selective NK defect with an intact lymphocyte ADCC function. Whether this defect will prove to be valuable in the assessment of a malignant transformation in a given patient will await further longitudinal NK studies and clinical follow-up of the patients.
Adult↗
Synergistic interaction between differentiation inducers and DNA synthesis inhibitors: a new approach to differentiation induction in myelodysplasia and acute myeloid leukaemia.
Numerous agents induce differentiation and maturation of neoplastic and dysplastic myeloid cells in vitro and some of these agents have been used with limited success in the treatment of patients with myelodysplastic syndromes (MDS) and myeloid leukaemias. We recently proposed that physiological and pharmacological agents which enhance differentiation and maturation in vitro act by two fundamentally different routes: (1) by hastening the progression through various differentiation/maturation steps; (2) by slowing proliferation (usually by inhibition of DNA synthesis). In order to test this thesis we looked for synergistic effects on differentiation using pairs of agents from the two groups in cultures of cells from myelodysplastic and acute myeloid leukaemia (AML) patients and from normal marrow donors. The results with three MDS, two AML and three normal samples show that combinations of differentiation inducing agents (retinoic acid, N-methylformamide) with DNA synthesis inhibitors (6-mercaptopurine, cytosine arabinoside and aphidicolin) produce a differentiation inducing effect equivalent to that of 10-100, or even 1000 fold higher concentrations of single agents. Myelotoxic effects in vitro were not synergistic. The use of these synergistic combinations should greatly enhance the usefulness of differentiation inducers in the therapy of MDS and myeloid leukaemia.
Antineoplastic Combined Chemotherapy Protocols↗
Cellular aspects of radiation leukemogenesis in C57 BL/Ka mice: alterations to thymic microenvironment and lymphopoiesis.
After a leukemogenic split dose course of irradiation, thymic nurse cells (TNCs) disappear. We have correlated this with the loss of an epithelial cell surface antigen (recognized by monoclonal antibody ER-TR3 and tentatively identified as Ia). In addition, epithelial cells have lost their capacity to interact with fetal thymocytes in vitro. Marrow grafting early after irradiation, that prevents the development of lymphomas, restores thymic nurse cells and thymocyte population. Such reconstitution and lymphoma prevention were not observed when marrow grafting was performed later (1 month after irradiation) during the preleukemic period.
Animals↗
Thymic lymphosarcomas obtained by X-rays in association with a weakly leukemogenic virus: cellular studies.
The association in C57BL/6 mice of a subleukemogenic radiation dose (1.75 Gy X 2) which induces 7% of thymic lymphosarcomas (TL) with the injection of a weakly oncogenic B-tropic retrovirus responsible for 5% of TL resulted in a higher incidence of TL (31%) than expected from a simple cumulative effect when the viral injection preceded the irradiations (VX protocol). When virus was injected after irradiation (XV protocol) TL incidence (19%) was not significantly different from that of a cumulative phenomenon. The B-tropic virus used (1223) was isolated from RadLV-Rs extract and cloned. The TL incidence correlates with the presence of virus firstly in the thymus and bone marrow (BM) during the preleukemic period, secondly in the cell lines established in vitro from TL obtained in both protocols. This suggests that B-tropic viruses derepressed by 4 radiation doses of 1.75 Gy might be similarly implicated in the mechanism of radio-induced TL. This hypothesis is further supported by the evidence that BM restoration inhibited leukemogenesis in processes induced either by 4 radiation doses of 1.75 Gy or by the association of 2 radiation doses and viral injection whereas it has no effect on TL induced by highly oncogenic thymotropic viruses. Transplantation of BM cells from animals which had been submitted shortly before to leukemogenic VX protocol failed to induce donor type TL or leukemias in irradiated recipients suggesting that preleukemic cells either are not present or cannot be detected. However a high incidence of recipient TL was observed indicating that viruses were transferred with the grafted cells.
Animals↗
t(3;5)(q21;q31) in a myelodysplastic syndrome.
Cytogenetic analysis from the bone marrow of a patient with a myelodysplastic syndrome revealed the balanced translocation t(3;5)(q21;q31). Although this translocation has recently been described in six cases of AML, this is the first such observation in a preleukaemic syndrome. Subsequent evolution into RAEB and AML(M2) was noted without the acquisition of additional cytogenetic changes and complete remission achieved with conventional cytotoxic chemotherapy. The relationships with other acquired abnormalities of chromosomes 3 and 5 in MDS/AML are discussed.
Adult↗
Pre-ALL and non-A, non-B hepatitis infection.
We report a case of acute lymphoblastic leukaemia which presented as hypoplastic anaemia following Non-A, Non-B viral hepatitis infection. The role of infection and the mechanisms involved in the evolution of pre-ALL to overt leukaemia remain speculative. However, it is of practical importance to distinguish pre-ALL from aplastic anaemia and the myelodysplastic syndromes during the early pancytopenic phase to avoid inappropriate management.
Anemia, Aplastic↗
The Ha-ras polymorphism in myelodysplasia and acute myeloid leukaemia.
We have assessed the possibility that rare allelic variants of the c-Ha-ras-1 locus may be linked to a susceptibility to malignancy [1]. c-Ha-ras-1 genotypes were scored in 41 patients with myelodysplasia (MDS), 51 patients with acute myeloid leukaemia (AML) and 52 normal subjects. The incidence of rare alleles in the MDS patients was 4.8% and in AML an incidence of 15.7% was found. No rare alleles were found in the normal subjects. We conclude that rare alleles in MDS are not a common predisposing factor.
Alleles↗
Growth of normal and malignant bone marrow cells.
Results of five different methods (heme breakdown, mitotic indices, total marrow cellularity and different methods of labelling indices) to determine bone marrow cell growth are reviewed. Normal immature erythroblasts and myeloblasts have generation times of about 5-10 h. Erythroblasts in neoplastic conditions (the myelodysplastic syndrome and polycythemia vera) have generation times which are significantly prolonged, by 12-75 per cent, but this may not be true for myeloblasts, since total labelling indices are increased (from normal 3.9 to 11.2 per cent) in the myelodysplastic syndrome. In contrast, generation times in aplastic anemia are significantly shortened, by about 70-80 per cent. Normal mature erythroblasts and promyelocytes have generation times of about 24 h, and the malignant prolongation may be even greater.
Anemia, Aplastic↗
Serum deoxythymidine kinase in adult T-cell leukemia-lymphoma and its related disorders.
Serum deoxythymidine kinase (TK) was measured in 15 patients with the acute type of adult T-cell leukemia (ATL), in 4 with chronic ATL, in 10 with lymphoma type ATL, in 9 with pre-ATL, in 11 with human T-cell leukemia virus type I (HTLV-I) associated with myelopathy (HAM) and in 19 HTLV-I carriers. All these patients were positive for anti-HTLV antibody. The level of TK in pretreatment serum was highest in acute ATL (15.6-1600 U/l, median 107 U/l). It was elevated in chronic ATL (5.4-55.0 U/l, median 37.6 U/l) and lymphoma ATL (6.8-316 U/l, median 16.8 U/l) but normal in pre-ATL (1.8-4.7 U/l, median 2.8 U/l), HAM (1.2-6.0 U/l, median 3.0 U/l) and HTLV-I carriers (1.1-4.6 U/l, median 2.3 U/l). Statistical examination revealed a significant difference between the levels of acute ATL and chronic ATL/lymphoma ATL. In the patients of this series, a close correlation between the level of TK and lactic dehydrogenase (LDH) was statistically present (p less than 0.01). These facts indicate that TK level is a useful indicator of the aggressiveness of ATL cells.
Acute Disease↗
Minimal diagnostic criteria for the myelodysplastic syndrome in clinical practice.
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Anemia, Refractory↗