Urinary excretion of beta-aminoisobutyrate and pseudouridine in acute and chronic myeloid leukemia.

End products of nucleic acid metabolism including beta-aminoisobutyrate (beta-AIB) and pseudouridine (psi-Urd) have been considered as potential biochemical markers for cancer. The urinary excretion of both metabolites was investigated in abnormal hematopoietic conditions including 26 patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) and was compared to that of 25 healthy controls. beta-AIB excretion in CML was directly correlated to the leukocyte count, the indicator of tumor cell mass. beta-AIB excretion was elevated in 27 and 75% of untreated AML and CML cases, respectively. Marrow blast cell content tended to correlate positively with psi-Urd excretion in AML. psi-Urd excretion was elevated in 82 and 87% of untreated AML and CML, respectively. Turnover of hematopoietic cells seemed to be a determinant for beta-AIB excretion, indicating higher cell turnover in CML patients compared to that in AML patients and in controls. With cytostatic treatment, excretion levels of beta-AIB and/or psi-Urd decreased after a transient rise.

Successful nonsibling bone marrow transplantation in severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) was diagnosed in a girl immediately after birth; her older brother had SCID and was successfully reconstituted by bone marrow transplantation from his uncle. She was isolated in a laminar air flow bench and decontaminated. The father differed by one HLA-A antigen but was HLA-Dw2 homozygous like the patient; his lymphocytes showed a slight response to the patient's cells in mixed lymphocyte culture (MLC). At the age of 2 1/2 months and again at 5 months, she was given a bone marrow transplant from the father. During the entire course the patient had no infections, and apart from a transient eosinophilia she had no signs of graft-versus-host reaction. Immunological reconstitution was nearly complete at 9 months of age, when she was recontaminated. One year later plasma immunoglobulin concentrations are in the low normal range (IgG and IgM) or decreased (IgA); tests of cell-mediated immunity are normal. Apart from slight upper respiratory infections, the patient has been healthy. Physical and psychological development have been normal.

A monoclonal antibody (NAT-9 II:3F-6F) that identifies a differentiation antigen on human myeloid cells.

A monoclonal antibody, designated NAT-9 II:3F-6F (IgM), was generated by hybridization of mouse myeloma cells with spleen cell from mice immunized with normal human bone marrow cells. The antibody reacted with 40-60% of bone marrow cells as analysed on samples from 40 normal individuals and only with a subpopulation of human acute myeloid leukemia (AML) cells of the M2 class (20/20 tested) and M4 class (12/12 tested) (subclasses of the French-American-British (FAB) classification), but not with leukemic cells of the M1 (0/12 tested) and M5 (0/12 tested) FAB subclasses. This is in contrast to many other myeloid-specific monoclonal antibodies. Fluorescence-activated cell sorter (FACS) analyses and morphological examination of cells stained with peroxidase as based on the NAT-9 II:3F-6F monoclonal antibody showed that this antibody reacted with a distant differentiation antigen which is absent on myeloblasts, but expressed on promyelocytes, myelocytes, metamyelocytes, band neutrophils, and on a minority of mature granulocytes. NAT-9 II:3F-6F did not bind to circulating monocytes, T and B cells, erythrocytes and a variety of different human cell culture lines. Immunoblotting demonstrated that the antibody bind to a cellular component with a Mr approximately 97.400 dalton. The antibody may be useful in immunological subclassification of non-lymphoid leukemias and in studies on hematopoiesis.

Acute leukaemia: development, remission/relapse pattern, relationship between normal and leukaemic haemopoiesis, and the 'sleeper-to-feeder' stem cell hypothesis.

Attention has been focused on two problems of acute leukaemia: (1) the origin of normal-appearing haemopoietic cells during relapse, and (2) the inverse relationship between leukaemic blast cell proliferation and useful haemopoietic cell production. The available evidence suggests that the normal-appearing cells during relapse may not all be remnants of normal haemopoiesis but may at least in part be derived from leukaemic cells. Although a differentiation defect is a major characteristic of acute leukaemia, it seems as if this defect is not absolute: some cells may succeed in differentiating more or less normally in spite of their descent from a leukaemic stem cell. Acute leukaemia is usually considered to be a primary white cell disorder which indirectly affects the other haemopoietic cell lines. It appears more likely, however, that acute leukaemia, at least the myeloid type, is a disorder of a stem cell common to granulocytopoiesis, erythropoiesis, and probably thrombocytopoiesis. Most descendants from the diseased stem cell fail to differentiate and remain at the blast cell level where they proliferate for some time; however, at a certain point proliferation ceases and the cells ultimately die. Another fraction of the progeny of the leukaemic stem cells may differentiate to some extent and may give rise to functionally useful cells. This is analogous to chronic myeloid leukaemia. The mechanism by which useful haemopoiesis apparently is suppressed in the presence of leukaemic blast cells has remained enigmatic so far. Previously suggested explanations which all assume some kind of cell-cell interaction by which normal haemopoietic cells succumb have neither been proved nor disproved. In this chapter, a new hypothesis is presented. It is assumed that some normal haemopoietic stem cells enter a dormant state at various distances in lineage from the fertilized ovum ('sleepers'). Another fraction of haemopoietic stem cells ('feeders') are actively proliferating and serve to feed the differentiating haemopoietic cell lines and to maintain the 'feeder' pool. When the 'feeder' pool is exhausted, a 'sleeper' cell is activated and sets up a new 'feeder' clone. Otherwise, 'sleepers' are protected against acting as 'feeders' in order to keep 'sleeper' divisions at a minimum and thus preserve their genetic information as intact as possible. It is suggested that the leukaemic event initially takes place in one or a few 'sleepers'. If the leukaemic 'sleeper' never succeeds in setting up a 'feeder' clone, clinical leukaemia will not develop. Clinical leukaemia will result if a leukaemic 'sleeper' establishes a leukaemic 'feeder' pool.(ABSTRACT TRUNCATED AT 400 WORDS)

Preleukemia: does it exist?

In acute myeloid leukemia (AML), many of the remaining normal-appearing cells exhibit various abnormalities. An interpretation is that these cells are descendants of leukemic cells which have succeeded in overcoming the major final differentiation block that exists in AML. Direct evidence is quoted that red cell precursors in AML are of leukemic descent and it is claimed that the target cell of AML is the pluripotent stem cell. Next, evidence has been compiled that all three cell lines (red cell, n. granulocytes, platelets) exhibit qualitative defects in "prelukemia." Hence it is postulated that preleukemia per se doses not exist but that preleukemic states which with a rather high frequency sooner or later end in overt AML are actually true leukemias that, however, differentiate reasonably well. Another way of phrasing it is that preleukemic states are AMLs that present in partial and sometimes long-lasting remission, which only after months to years lose their differentiation ability and then are classified as AML.

A case of 'auto-immune thrombocytopenic purpura' serologically similar to post-transfusion purpura.

The report describes a HPA-1a (Zwa)-negative woman with thrombocytopenia and antibodies in serum and eluate from autologous platelets with an operational anti-HPA-1a specificity. The results of the serological investigations were similar to the findings in most patients suffering from post-transfusion purpura. However, the present patient had no history of blood transfusion prior to the unset of purpura and the thrombocytopenia had persisted 6 months before splenectomy.

Cell proliferation and protein synthesis in human leukaemic myeloblasts after cytosine arabinoside therapy.

The effect of a single intravenous bolus injection of cytosine arabinoside (ARA-C) on the cytokinetics and 3H-leucine uptake of leukaemic myeloblasts in bone marrow and blood was studied at intervals up to 96 h after ARA-C in five patients with previously untreated acute myelogenous leukaemia. An early decrease in mitotic index and in 3H-thymidine labelling was observed in four of five patients and pretreatment values were reached again within the observation period. Changes suggesting synchronization were not observed. ARA-C induced a marked decrease in protein synthesis in the leukaemic myeloblasts as estimated from either a decrease in the 3H-leucine labelling index or the mean grain count of 3H-leucine labelled cells. It is suggested that ARA-C is incorporated also by cell which are not in S-phase and has a prolonged biochemical effect on the leukaemic cells.

Nuclear DNA-polymerase estimation in human leukaemic myeloblasts.

A technique which detects the presence of DNA-polymerase in cell nuclei by measuring the incorporation of 3H-thymidine-5-triphosphate (3H-TTP) has been used to estimate the proportion of leukaemic myeloblasts which contains DNA-polymerase and DNA capable of acting as primer-template. In six cases of previously untreated acute myeloid leukaemia the 3H-TTP labelling index (3H-TTP LI) was much larger than the fraction in DNA synthesis. After a single 'flash' injection of cytosine arabinoside a pronounced decline was observed in the 3H-TTP LI, which can be explained by a direct inhibition of NDA-polymerase. No change was observed in the fraction of cells labelled with 3H-thymidine. A decrease in 3H-TTP LI was also observed after a single i.v. dose of methotrexate.

Cytoplasmic labelling of eosinophils with tritiated thymidine triphosphate.

A new technique which detects the presence of DNA polymerase and primer-template DNA by measuring the incorporation of 3H-thymidine-5-triphosphate (3H-TTP) showed cytoplasmic labelling of eosinophilic granulocytes and eosinophilic myelocytes in normals, in acute leukaemia, in chronic myeloid leukaemia and in patients with eosinophilia of unknown origin.

Post-transfusion purpura (PTP) due to anti-Zwb (-PlA2): the significance of IgG3 antibodies in PTP.

The first two patients with post-transfusion purpura (PTP) due to platelet antibodies against the Zwb antigen are reported. The anti-Zwb specificity could be demonstrated only with an enzyme-linked immunosorbent assay (ELISA) but not with the immunofluorescence or the complement fixation test due to coexistent potent multispecific HLA antibodies. One of the patients had never received blood transfusion until 24 d before the development of thrombocytopenic purpura. In both patients, anti-Zwb of IgG1 and IgG3 subclasses defined by monoclonal antibodies were present during the thrombocytopenic period but the antibodies of IgG3 subclass disappeared concomitantly with clinical improvement. The association between the IgG3 subclass of anti-Zw antibodies and the destruction of autologous platelets in Zw-immunized individuals was investigated further. All of four PTP patients had anti-Zw antibodies of the IgG1 and IgG3 subclasses during the thrombocytopenic period while all of 20 mothers of children affected with alloimmune neonatal thrombocytopenia (AINT) had anti-Zwa of only the IgG1 and not IgG3 subclass at the time of delivery of thrombocytopenic children (P less than 10(-4). Thus, the destruction of autologous platelets in PTP is associated with the presence of anti-Zw of the IgG3 subclass which may be of importance in the pathogenesis of PTP.