Toxicity and bone marrow response of patients with hairy cell leukemia treated with biosynthetic (recombinant) alpha-2-interferon.
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Adult↗
Biomedical subjects
D W Golde
Publications and source records attributed to D W Golde.
Pure red cell aplasia characterized by erythropoietic maturation arrest. Response to anti-thymocyte globulin.
Pure red cell aplasia is a syndrome characterized by markedly decreased erythropoiesis. On bone marrow examination, there are typically less than 0.5 percent erythroblasts, but sometimes a picture of maturation arrest can be seen. This report describes a patient with maturation arrest of erythropoiesis at the basophilic normoblast stage who had a response to an eight-day course of anti-thymocyte globulin with a return of normal erythropoiesis.
Adult↗
Complete nucleotide sequence of an infectious clone of human T-cell leukemia virus type II: an open reading frame for the protease gene.
The entire nucleotide sequence of an infectious clone of human T-cell leukemia virus type II provirus was determined. This provirus consists of 8952 nucleotides. In addition to long terminal repeats and gag, pol, env, and X, a protease gene that is responsible for processing the gag precursor protein was found. The protease gene is encoded in a different frame from gag and pol and was located between the gag and pol open reading frames. The 5' region of the protease gene overlaps the 3' gag region. Coding regions of the provirus show about 60% homology with those of human T-cell leukemia virus type I at the nucleotide level. The evolutionary relationship between human T-cell leukemia virus types I and II is discussed.
Antigens, Viral↗
Purification and characterization of a human T-lymphocyte-derived glial growth-promoting factor.
Antigen- or lectin-stimulated T lymphocytes and human T-cell leukemia virus (HTLV)-infected cell lines secrete lymphokines that can influence the growth and function of a variety of cell types. We recently demonstrated that supernatants from the HTLV-II-infected Mo-T-cell line stimulate the proliferation of rat brain oligodendrocytes and astrocytes. We have now purified a glial growth-promoting factor (GGPF) from these supernatants. Purification from serum-free conditioned medium was accomplished by sequential concentration, ammonium sulfate precipitation, lentillectin affinity chromatography, gel filtration, and reversed-phase high-performance liquid chromatography. GGPF is assayed by its ability to stimulate DNA synthesis in oligodendrocytes, as measured by [3H]thymidine uptake. The purified GGPF has an apparent Mr of 30,000 when analyzed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis under nonreducing conditions. Under reducing conditions, however, GGPF appears as a single band of Mr 18,000. Both reduced and unreduced forms have biological activity, suggesting that GGPF exists in both a functional monomeric and dimeric form. Purified GGPF appears to be a biochemically and functionally distinct lymphokine.
Animals↗
Autoimmune disease in hairy-cell leukaemia: clinical syndromes and treatment.
Thirty-seven patients with hairy-cell leukaemia were retrospectively reviewed for the presence of autoimmune disease. Ten definite and two probable cases were identified; these patients had positive serologies (immune complexes, antinuclear antibodies or rheumatoid factor) or biopsy-proven vasculitis. Clinically, two distinct syndromes were recognized. Six patients had joint symptoms, usually associated with nodular skin lesions; all responded promptly to therapy. Four additional cases had a more severe disease consisting of fevers, malaise, weight loss, skin rash, and variable visceral involvement; there was one death in this group. There appeared to be no relationship between presence of vasculitis and the severity or progression of the underlying malignant disease. We conclude that autoimmune disease is much more frequent in hairy-cell leukaemia than has previously been recognized, and that the outcome in these syndromes is usually good. Although the autoimmune syndrome generally responds promptly to splenectomy, corticosteroids, or cytotoxic therapy, failure to recognize this complication may lead to increased morbidity and occasional mortality.
Autoimmune Diseases↗
Separation by velocity sedimentation of human haemopoietic precursors forming colonies in vivo and in vitro cultures.
Cells which give rise to granulocyte-macrophage colonies under the influence of peripheral blood white cells (CFU-c (WBC] and Mo T cell conditioned medium (CFU-c (Mo] sedimented at a faster rate than the cells which form mixed erythroid-granulocytic colonies in methylcellulose in vitro (CFU-mix) and granulocytic (CFU-dg) and megakaryocytic (CFU-dm) colonies in diffusion chambers in mice. Despite identical peak sedimentation rate for the two CFU-c populations, sedimentation profiles suggest that they are heterogeneous with respect to size. A proportion of CFU-c (Mo) may be identical with CFU-dg and CFU-mix. Sedimentation profiles for cells which give rise to mixed colonies in vitro (CFU-mix) and to granulocytic colonies in diffusion chambers in cyclophosphamide pretreated mice (CFU-dg (CY] and in Mo conditioned medium treated mice (CFU-dg (Mo] were similar. On the average CFU-dm sedimented somewhat slower than CFU-dg. These and other observations suggesting a close relationship between CFU-dg and multipotential haemopoietic precursors are discussed.
Bone Marrow Cells↗
Diminished in vitro responsiveness of circulating erythroid progenitor cells to insulin as an indicator of insulin resistance.
While insulin resistance is considered characteristic of extreme obesity, it may be more difficult to demonstrate in less severe forms of obesity. We studied five moderately obese individuals [mean body mass index (MBMI), 34.1 +/- 1.85 (+/- SE) kg/m2], one massively obese patient (BMI, 50.2 kg/m2), and seven age-matched normal subjects (MBMI, 22.4 +/- 0.93 kg/m2). While two of the obese patients had normal glucose tolerance, all had fasting hyperinsulinemia (P less than 0.02 vs. normal subjects) and exaggerated insulin responses after oral glucose challenge, as defined by area under the 3-h insulin response curve (P less than 0.01 vs. normal subjects). That this hyperinsulinemia represented in vivo insulin resistance was supported by the glucose and insulin responses in four individuals to an iv glucose bolus analyzed by the minimal modeling technique. Study of monocyte insulin receptors revealed no reduction in total insulin binding in the four obese patients tested. Since physiological concentrations of insulin stimulate the in vitro growth of normal human erythroid progenitor cells (EPC), we reasoned that this response might be blunted in cells from individuals with endogenous insulin resistance. The mean peak EPC proliferative response (26.7 +/- 9.11% above baseline) in the obese hyperinsulinemic group was significantly less than the corresponding mean value in the control group (92.6 +/- 5.24% above baseline, P less than 0.001). These results suggest that the minimal modeling technique is a sensitive method for the in vivo demonstration of insulin resistance in moderately obese individuals and that EPC responsiveness to physiological concentrations of insulin reflects in vivo insulin sensitivity and may be used as an in vitro indicator of insulin resistance.
Adolescent↗
Chronic myelogenous leukemia: recent advances.
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Bone Marrow Transplantation↗
Human T-cell leukemia virus x gene.
The human T-cell leukemia virus (HTLV) types I and II are associated with specific hematological cancers. These viruses rapidly transform normal T-lymphocytes in vitro. The mechanism of HTLV-induced leukemogenesis is unknown. Structural analysis of HTLV-I and HTLV-II has revealed sequences of unknown function, termed X, at the 3' end of the proviral genome. The distal two-thirds of the X sequences are highly conserved between HTLV-I and HTLV-II. We have shown that these conserved X sequences contain a gene, termed x, that is expressed in both HTLV-I and HTLV-II by identifying a subgenomic X RNA as well as the proteins encoded by these messages. The function of this unique x gene is unknown; however, its conservation and expression suggest that it may play a role in HTLV replication and in HTLV-induced leukemogenesis.
Cell Line↗
Biological activities of human granulocyte-macrophage colony-stimulating factor.
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Biological Assay↗
Recombinant alpha-2-interferon for hairy cell leukemia.
Twenty-two patients with hairy cell leukemia were treated with biosynthetic (recombinant) alpha-2-interferon in an open-label, single-arm efficacy study. Patients received 2 X 10(6) U/m2 recombinant alpha-2-interferon three times weekly. Therapy was well tolerated subjectively with minimal short-term hematologic toxicity. Two patients had bacterial infections during the period of study, and one patient experienced a short-lived readily reversible rejection of a corneal transplant. Statistical comparison of the mean hematologic indices at study entry and after three to six months of therapy with recombinant alpha-2-interferon indicates a significant improvement in hemoglobin, granulocyte, and platelet counts. Bone marrow biopsies in six of 14 patients after six months of therapy showed a greater than 50% decrease in the infiltration of leukemia cells. We conclude that recombinant alpha-2-interferon is highly effective therapy for hairy cell leukemia.
Adult↗
Characterization of purified human erythroid-potentiating activity.
Erythroid-potentiating activity (EPA), purified from serum-free medium conditioned by the Mo human T-lymphoblast cell line, is a 28,000 dalton glycoprotein. Removal of carbohydrate from EPA by digestion with endoglycosidase F generates a protein with an apparent molecular weight of 18,000. We have used purified EPA to develop rabbit antisera which neutralize the burst-promoting activity of purified EPA. These antisera immunoprecipitate a 28,000-dalton glycoprotein from metabolically labeled Mo cells. Purified EPA stimulates murine and human BFU-E and CFU-E but not myeloid or macrophage colonies.
Animals↗
Detection of two distinct malignant B cell clones in a single patient using anti-idiotype monoclonal antibodies and immunoglobulin gene rearrangement.
Immunoglobulin gene rearrangement analysis and somatic cell hybridization techniques were used to examine the malignant cell population in an unusual patient with hairy cell leukemia and macroglobulinemia (N Engl J Med 296:92, 1977). Although previous investigations suggested that the IgM macroglobulin was secreted by the circulating leukemia cells, anti-idiotype monoclonal antibodies raised to the IgM macroglobulin failed to react with the malignant cells in the circulation and bone marrow. In contrast, approximately 50% of the mononuclear cells from an enlarged inguinal lymph node reacted strongly with the anti-idiotype antibodies. Subsequent reanalysis of all cell populations demonstrated that whereas the circulating and bone marrow cells were IgM kappa-bearing, the macroglobulin was IgM gamma-bearing and the lymph node cells were evenly divided among IgM kappa-bearing and IgM gamma-bearing. Immunofluorescence flow cytometry indicated that those lymph node cells that reacted strictly with the anti-idiotype antibody were IgM gamma-bearing, demonstrating that they were the source of macroglobulin. An analysis of immunoglobulin gene DNA confirmed the coexistence of two distinct malignant B cell populations in the lymph node and indicated that the IgM kappa-bearing lymph node cells were identical to the circulating and bone marrow leukemic cells.
Aged↗
Purified human granulocyte-macrophage colony-stimulating factor: direct action on neutrophils.
Neutrophil migration inhibition factor from T lymphocytes (NIF-T) is a lymphokine that acts to localize granulocytes. Medium conditioned by the Mo human T-lymphoblast cell line was used to purify NIF-T, a glycoprotein with a molecular weight of 22,000. The NIF-T was found to potently stimulate the growth of granulocyte and macrophage colonies from human bone marrow and colony formation by the KG-1 myeloid leukemia cell line. Thus a human lymphokine (NIF-T) that modulates the activities of mature neutrophilic granulocytes is also a colony-stimulating factor acting on precursors to induce growth and differentiation of new effector cells.
Bone Marrow Cells↗
Expression of the 3' terminal region of human T-cell leukemia viruses.
Human T-cell leukemia viruses (HTLV) are closely associated with some human T-cell leukemias and lymphomas. A unique 3' region of the HTLV genome is believed to be involved in HTLV-induced cellular transformation, although the function of this region has yet to be determined. A subgenomic messenger RNA transcribed from this region of HTLV has now been characterized. These results provide direct evidence for the expression of a novel gene in HTLV.
Base Sequence↗
Identification of the putative transforming protein of the human T-cell leukemia viruses HTLV-I and HTLV-II.
The human T-cell leukemia viruses HTLV-I and HTLV-II are unique among the transforming retroviruses of vertebrates in their ability to transform human T cells in vitro and in their close association with human malignancies (T-cell lymphomas and leukemia). Their genomes are relatively simple, containing the genes gag, pol, env, and a 3' region termed "X." This 3' region may be responsible for the transforming potential of the viruses. The existence of proteins encoded by the 3' region has been postulated on the basis of multiple open reading frames. In the present study this region is shown to contain a gene encoding a protein of 40 kilodaltons in HTLV-I and 37 kilodaltons in HTLV-II. It is proposed that these proteins be called, respectively, p40xI and p37xII.
Amino Acid Sequence↗
Purification and characterization of human T-lymphocyte-derived erythroid-potentiating activity.
The human T-lymphoblast cell line, Mo, secretes a number of lymphokines, including erythroid-potentiating activity (EPA), an important early regulator of erythropoiesis. We report purification of EPA to homogeneity, from serum-free Mo-conditioned medium. Purification was accomplished by sequential concentration, ammonium sulfate precipitation, lentil lectin affinity chromatography, gel filtration, and reverse-phase high-performance liquid chromatography. EPA was assayed by its ability to stimulate the growth of large erythroid colonies (bursts) from normal human peripheral blood. The purified EPA has a molecular weight of 28,000 and appears as a single band when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing or nonreducing conditions. Purified EPA stimulates the growth of both early and late erythroid precursors from human bone marrow, as well as colony formation by the K562 human erythroleukemia cell line. Purified EPA has no colony-stimulating factor activity nor does it appear to be a structural protein of the human T-cell leukemia virus subtype II which infects the Mo cells.
Bone Marrow↗
Hairy cell leukemia. Disease pattern and prognosis.
The authors reviewed the clinical course of 31 consecutive patients with hairy cell leukemia seen at the University of California Los Angeles. The clinical presentation included varying degrees of pancytopenia, splenomegaly, and bone marrow infiltration with hairy cells. Ten patients were identified as having an "atypical" disease, which is defined as absence of palpable splenomegaly and/or marrow cellularity of less than 45%. These atypical patients had clinically milder disease and significantly less anemia than the usual patient (mean hemoglobin, 12.1 g/dl versus 9.4 g/dl; P = 0.016), although neutropenia and thrombocytopenia were comparable. Mortality and infection rates were similar in both groups. Infections were common in all patients, but opportunistic infections and septicemia were rare in patients prior to initiation of therapy. Two thirds of the patients who received corticosteroids and/or cytotoxic agents had serious infections, with a 50% mortality rate. Nearly 70% of the neutropenic patients (leukocyte count less than 1000) who received any form of treatment had a serious infection. The most important factors predicting mortality were chemotherapy and an age older than 50 years. Patients who survived 2 years with their disease had an excellent prognosis, and four patients in this series are alive and well with their disease for more than 10 years.
Adult↗