Leukaemia and transient leukaemia in Down syndrome

Summary We have reviewed 215 published cases of leukaemia and transient leukaemia in Down syndrome. There is an over-representation of mosaic trisomy 21, possibly the result, at least in part, of a survival effect. The most intriguing observation is a bimodal distribution of maternal age, produced largely because cases with true leukaemia have a significantly higher maternal age than cases with transient leukaemia (33.5 versus 29.5 years). In conjunction with evidence that meiosis I non-disjunction is infrequent in transient leukaemia, this suggests different mechanisms for the etiology of leukaemia and transient leukaemia, and favours a locus predisposing to transient leukaemia proximal to the centromere on the long arm of chromosome 21.     

Cytochemistry of leukocytes in children. IV. The use of cytochemical tests in the differentiation and prognostic evaluation of acute leukemias]

From 63 children with acute leukaemia the bone-marrow smears were cytochemically examined before the beginning of therapy. The activity of peroxydase was examined according to Sato and Sekya, that of acid phosphatase according to L?ffler and Berghoff, that of alpha-naphthyl-acetate-esterase according to Gomori; the evidence of glycogen was examined by means of the PAS-diastase response according to McManus. Among the 63 cases of leukaemia we found 6 cases of paramyeloblastic leukaemia, 2 cases of parapromyelocytic leukaemia, and 3 cases of myelomonocytic leukaemia. 52 cases of leukaemia could not be further differentiated in morphological respect. They represented an immature paraleukoblastic leukaemia. A division according to leading cytochemical criteria was made for them. The therapeutic possibility of influencing the various groups was checked by means of prolonged observations. Children affected with paraleukoblastic leukaemia of the phosphatase type had a significantly low rate of remission similar to the myeloid leukaemia. Paraleukoblastic leukaemia of the PAS type, esterase type and the undifferentiated type revealed no essential differences. The rate of remission, however, was highest in leukaemia of the PAS type amounting to 100%. In one part of patients the prolonged cytochemical observations in 8 children with recidives showed that the cytochemical type under chemotherapy was changed.     

The effect of exogenous alkalization on cytokinetics and on the survival rate of mice with lymphoblastic leukemia]

In mice vaccinated with two forms of lymphoblastic leukaemia and alkalized with intravenous administration of sodium bicarbonate, the survival rate, the extent of leukaemic infiltration and the proliferative capacity of cells in the bone-marrow, thymus, spleen, lymphnodes, liver and lungs were investigated. The survival rate in the TAL leukaemia of the AKR stem producing an endogenous acidosis could be significantly prolonged in a statistical way by alkalization. Yet an accelerated expiring rate could be observed after exogenous alkalization in L-1210 leukaemia of the DBA/2J stem producing an endogenous alkalosis. By means of cytological and impulse-cytophotometrical investigations the exogenous alkalization of both forms of leukaemia could be proved to have a direct bearing on the proliferative kinetics. In TAL leukaemia the leukaemic proliferation was inhibited by the exogenously involved correction of the acid-base balance; in the L-1210 leukaemia, however, the pH disturbances were enhanced, thus accelerating the leukaemic proliferation. Consequently, the disturbances of the acid base balance seem to be an essential cofactor in the leukaemia genesis. The exogenous direction of the acid-base balance may be important as a means of treating leukaemia.     

Comparison of the cytomorphological classification with the cytochemical differentiation of acute lymphatic leukemia in children]

In 100 children with acute lymphatic leukaemia the cytomorphological subclassification of the pathological cell type was made according to Mathé and the French-American-British Co-operative group (FAB). In addition, all cases of leukaemia were differentiated according to their cytochemical type. Lymphoblasts from 10 cases of leukaemia could be subclassified immunologically. From 71 children will ALL the survival rates of those cases of leukaemia subclassified cytomorphologically and the cytochemical reactions were compiled and partially compared. Microlymphoblastic leukaemia could be found to be the most frequent type of ALL at children's age. Prolymphocytic leukaemias were characterized by a favourable survival rate and the highest percentage of ALL with the PAS type. Macrolymphoblastic and microlymphoblastic cases of leukaemia revealed no essential differences of survival rate, but significant differences of cytochemical reactions.     

A comparison of the Antileukaemic Effects of Recombinant Human Tumour Necrosis Factor-alpha and its Muteins on Leukaemia L1210 and Leukaemia P388 in Mice

We investigated the influence of recombinant human tumour necrosis factor alpha (TNF-alpha) and its derivatives termed muteins III, V, VI-in which the first 3 to 7 amino acids of native TNF-alpha have been replaced-on the survival time of mice inoculated with leukaemia L1210 or leukaemia P338. TNF-alpha prolonged the survival of mice with leukaemia L1210 but did not have any therapeutic activity in leukaemia P388-bearing mice. Muteins-treated mice with leukaemia P388 lived longer than animals receiving TNF-alpha, while those inoculated with leukaemia L1210 did not show any significant prolongation of life compared with the TNF-alpha treated group. The results presented in this report indicate that the antileukaemic activity of TNF-alpha is governed at least in part by the nature of the N-terminal amino acids.     

Plasma transcobalamins in haematological disorders

Plasma UBBC-B12 and transcobalamins were measured in 112 patients suffering from different haematological disorders. The data showed different patterns of changes in plasma transcobalamin profile in different haematological disorders. Plasma UBBC-B12 and transcobalamins were significantly higher than normal in untreated chronic myeloid leukaemia, acute promyelocytic leukaemia, nutritional megaloblastic anaemia and in refractory anaemias with hypercellular marrow. Normal levels of these proteins were noted in chronic lymphatic leukaemias, in primary and secondary hypereosinophilic states and in multiple myeloma. Subnormal levels of these proteins were observed in hypoplastic anaemia and acute lymphoblastic leukaemia. Chronic myeloid leukaemia patients during blast crisis and acute myeloid leukaemia patients except those suffering from acute promyelocytic leukaemia showed varying pattern of plasma transcobalamins depending on type of blast crisis or FAB subtype of AML. The significance of these changes in plasma transcobalamins have been discussed along with the experience of other workers in this field.     

Src kinase signaling in leukaemia

Role of Src kinases in acute lymphoblastic leukaemia has been recently demonstrated in leukaemia mouse model. Retained activation of Src kinases by the BCR-ABL oncoprotein in leukaemic cells following inhibition of BCR-ABL kinase activity by imatinib indicates that Src activation by BCR-ABL is independent of BCR-ABL kinase activity and provides an explanation for reduced effectiveness of the BCR-ABL kinase activity inhibitors in Philadelphia chromosome-positive acute lymphoblastic leukaemia. Simultaneous inhibition of kinase activity of both BCR-ABL and Src kinases results in long-term survival of mice with acute lymphoblastic leukaemia. Leukaemic stem cells exist in acute lymphoblastic leukaemia, and complete eradication of this group of cells would provide a curative therapy for this disease.     

Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L

Chromosomal translocation is a common cause of leukaemia and the most common chromosome translocations found in leukaemia patients involve the mixed lineage leukaemia (MLL) gene. AF10 is one of more than 30 MLL fusion partners in leukaemia. We have recently demonstrated that the H3K79 methyltransferase hDOT1L contributes to MLL-AF10-mediated leukaemogenesis through its interaction with AF10 (ref. 5). In addition to MLL, AF10 has also been reported to fuse to CALM (clathrin-assembly protein-like lymphoid-myeloid) in patients with T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML). Here, we analysed the molecular mechanism of leukaemogenesis by CALM-AF10. We demonstrate that CALM-AF10 fusion is both necessary and sufficient for leukaemic transformation. Additionally, we provide evidence that hDOT1L has an important role in the transformation process. hDOT1L contributes to CALM-AF10-mediated leukaemic transformation by preventing nuclear export of CALM-AF10 and by upregulating the Hoxa5 gene through H3K79 methylation. Thus, our study establishes CALM-AF10 fusion as a cause of leukaemia and reveals that mistargeting of hDOT1L and upregulation of Hoxa5 through H3K79 methylation is the underlying mechanism behind leukaemia caused by CALM-AF10 fusion.     

Recognition of Leukaemia Cells as Foreign before and after Autoimmunization

Leukaemia cells in the peripheral blood of nine patients with acute leukaemia were removed and stored. When the patients had been brought into haematological remission these leukaemia cells were cultured with autologous lymphocytes both before and after the patients had been autoimmunized with their own irradiated leukaemia cells. The extent to which the leukaemia cells stimulated the “normal lymphocytes” was increased as the result of autoimmunization.The implications of the use of this test for determining the best regimen for “immunotherapy” in acute leukaemia are discussed.     

Gonadal function in men treated for acute leukaemia.

Gonadal function was assessed in eight men in remission of leukaemia who had completed treatment eight months to eight years previously. All four men treated for acute myeloid leukaemia had normal sperm counts and motility, compared with only one of the four with acute lymphatic or undifferentiated leukaemia. Hormonal studies indicated that the sterility resulted from gonadal failure rather than pituitary dysfunction after cranial irradiation. These findings are important in the counselling of patients with leukaemia.     

Risk of acute childhood leukaemia in Sweden after the Chernobyl reactor accident. Swedish Child Leukaemia Group.

OBJECTIVE--To evaluate the risk of acute childhood leukaemia in areas of Sweden contaminated after the Chernobyl reactor accident in April 1986. DESIGN--Population based study of childhood leukaemia diagnosed during 1980-92. SETTING--Coordinates for places of residence of all 1.6 million children aged 0-15 years; aerial mapped areas of Sweden heavily contaminated after the Chernobyl accident. SUBJECTS--888 children aged 0-15 years with acute leukaemia diagnosed in Sweden during 1980-92, identified with place of birth and residence at diagnosis. MAIN OUTCOME MEASURES--Risk of leukaemia in areas contaminated after the Chernobyl accident compared with the rest of Sweden and in the same areas before the accident. RESULTS--During six and a half years of follow up after the accident the odds ratio for acute leukaemia was 0.9 (95% confidence interval 0.6 to 1.4) in highly contaminated areas (> or = 10 kBq/m2) compared with the same areas before the accident. For the subgroup acute lymphoblastic leukaemia in children aged under 5 years at diagnosis the odds ratio was 1.5 (0.8 to 2.6). For all cases diagnosed after May 1986 in highly contaminated areas compared with areas of low contamination the odds ratio was 0.9 (0.7 to 1.3). For acute lymphoblastic leukaemia in children aged under 5 years at diagnosis the odds ratio was 1.2 (0.8 to 1.9) in highly contaminated areas compared with areas of low contamination. Dose-response analysis showed no correlation between the degree of contamination and the incidence of childhood leukaemia. CONCLUSION--There has been no significant increase in the incidence of acute childhood leukaemia in areas of Sweden contaminated after the Chernobyl reactor accident.     

Acute leukaemia and the same chromosome abnormality in monozygotic twins

Summary Monozygotic twin girls, both of whom had acute undifferentiated leukaemia and a 47,XX,+19 karyotype, are described. The case is discussed in terms of childhood leukaemia and the hypothesis that a single transformation event in utero may be responsible for leukaemia in twins.     

Leukaemia and smoking habits among United States veterans.

The relation between leukaemia and smoking habits was examined in data from the veterans'' smoking study, a prospective study of mortality among 248,000 United States veterans, of whom 723 died of leukaemia during 1954-69. A significant increase in mortality from leukaemia among cigarette smokers (relative risk 1.53) was found, together with a dose-response relation with amount smoked (trend p less than 0.001). The relation was strongest (relative risk 1.72) for monocytic and chronic and unspecified myeloid leukaemias (ICD (7th revision) codes 204.1 and 204.2). For these leukaemias the increase was almost twofold (relative risk 1.93) among current smokers of over 20 cigarettes daily. Ex-cigarette smokers also showed an increase of leukaemia (relative risk 1.39; p less than 0.001). These findings are consistent with other studies and relevant to the interpretation of minor increases of leukaemia both in population and in individual based studies. If causal they also imply that smoking is responsible for many more deaths from leukaemia in adults than all other known causes combined.     

Adenosine deaminase activity in leukemia patients

The activities of adenosine deaminase (ADA) were measured in the blood plasma, erythrocytes, and lymphocytes of healthy reference persons and in patients affected with leukaemia. ADA is increased in patients with acute immature cell leukaemia, in patients with chronic lymphatic leukaemia it is comparatively low in lymphocytes. In chronic myeloic leukaemia ADA activities are different depending on the activity of the disease. ADA-activities in the blood plasma, erythrocytes, and lymphocytes do not correlate with each other. ADA-activities in leukaemias may be regarded as an indicator of increased purin metabolism rather a as parameter of disturbed cellular immunofunction.     

Vincristine and Prednisone for the Induction of Remissions in Acute Childhood Leukaemia

A total of 65 children with acute lymphoblastic leukaemia and seven with other types of acute leukaemia received treatment with a combination of vincristine and prednisone. In all 122 courses of treatment were given. Of 22 patients with acute lymphoblastic leukaemia who received this as their first treatment, all achieved complete remission. The complete remission rates were 82% for patients with acute lymphoblastic leukaemia in their first relapse, 63% in the second relapse, and much lower in subsequent relapses and in the patients with other types of acute leukaemia. Alopecia and gastrointestinal and neuromuscular toxicity occurred respectively in 51%, 29%, and 21% of instances, only the last of these side-effects of vincristine being dose-related. Most of the complete remissions were obtained with a total dose of vincristine which carried only a low risk of neurotoxicity.     

Feline Leukaemia Viral Antigens and Antisera to the Group Specific Antigens of the Murine Leukaemia Viruses

GEERING et al.¹ reported that feline leukaemia viruses shared one of the group specific antigens of the murine leukaemia viruses, gs-3, as detected by immunoprecipitation in agar gels with broadly reactive rat antisera to the group specific antigens of the murine leukaemia viruses (MuLV). Subsequently, they found that this shared group specific antigen was also present in the hamster and rat C-type viruses². Work by Schafer³ and our own immunodiffusion⁴ and complement fixation studies have confirmed the immunological reactivity between the feline leukaemia viral antigens and broad-reacting murine leukaemia group specific antisera. We have now applied this interspecies immunological reaction between the murine and feline C-type viruses to quantitative studies of the feline leukaemia viruses. Broad-reactive murine leukaemia-sarcoma group specific antisera prepared in rats by the induction of murine sarcoma virus (MSV) tumours^{5, 6} were found to be as useful and nearly as sensitive as a feline leukaemia-sarcoma specific, group specific antiserum for the in vitro detection and assay of the noncytopathogenic feline leukaemia virus (FeLV).     

Phagocytic granulocyte function in hemoblastoses]

Judging from the spontaneous NBT reduction, the indices of phagocytosis and NBT, there is a moderate, but statistically significant diminution of these parameters in leukaemia and malignant lymphoma including plasmocytoma. Moreover, further diminutions could be identified during the acute stage of the disease (first diagnosis or recidive) in acute leukaemia and lymphogranulomatosis, but not for chronic myeloic leukaemia.     

Decreasedin vitro chemosensitivity of tumour cells in patients suffering from malignant diseases with a poor prognosis

The aim of the study was to assess the predictive value of MTTin vitro assay for evaluation of tumour cell resistance/sensitivity to cytotoxic drugs. We analyzed 105 samples of malignant cells of different origin. The study included patients with a diagnosis of acute and chronic lymphatic leukaemia, acute and chronic myeloid leukaemia, non-Hodgkin lymphoma, carcinoma of the lung, stomach and liver, rhabdomyosarcoma and breast carcinoma. The results demonstrate outstanding chemosensitivity in the majority of childhood acute lymphoblastic leukaemias, medium chemosensitivity of adult haematopoietic malignant diseases and chemoresistance of solid tumour cells. Our preliminary data suggest a good correlation betweenin vitro MTT assay and clinical curability of individual malignant diseases.Abbreviations ALL acute lymphoid leukaemia - AML acute myeloid leukaemia - CML chronic myeloid leukaemia - LCS₅₀ 50% leukaemic cell survival     

Direct evidence for the cell surface location of a protease-inhibitor complex on intact leukaemia cells

The interaction of a protease with two fluorescent inhibitors has been studied using intact fixed leukaemia cells as the source of the membrane bound enzyme. Fresh rat leukaemia cells were disrupted and the cytosol collected; this extract was known to contain a protein inhibitor of guanidinobenzoatase (GB) associated with leukaemia cells. All the cytosolic proteins were derivatised with Texas red acid chloride. Leukaemia cells with latent GB failed to bind the Texas red inhibitor protein but did so after activation of GB. Competition experiments with 9-amino acridine (a fluorescent marker for the active site of GB) demonstrated that the Texas red-inhibitor protein could only bind to intact leukaemia cells when the active centre of GB was not already occupied by 9-amino acridine. This competition between these two fluorescent inhibitors demonstrated their specificity for GB. The use of intact leukaemia cells and the high molecular weight of the inhibitor protein precludes the possibility of any interaction between GB and inhibitor within the cells. It is concluded that GB and the GB-inhibitor complex of latent GB are located on the external surface of intact leukaemia cells.