Heterogeneity in acute myeloblastic leukemia.

Morphological-identified blast populations are the hallmark of the malignant clones that dominate hemopoiesis in acute myeloblastic leukemia (AML). Marked heterogenity is characteristic of AML blasts. Patient-to-patient variation is seen in their biological properties but is particularly evident in the response to treatment.

Structure of T cell antigen receptor beta chain in synovial fluid cells from patients with rheumatoid arthritis.

We attempted to identify a clonal proliferation of T cells from synovial fluid samples from patients with rheumatoid arthritis, using techniques of restriction fragment length polymorphism. We used probes for the beta chain of the T cell receptor to analyze restriction fragments prepared from the genomic DNA of synovial fluid mononuclear cells from 10 patients and synovial fluid T cell preparations from 5 additional patients. The results demonstrated unarranged (germline) T cell receptor gene fragments of DNA in all cell preparations, indicating the lack of clonality of rheumatoid arthritis synovial fluid T cells.

T cell receptor delta gene rearrangements in acute lymphoblastic leukemia.

Using a newly isolated cDNA clone encoding the TCR-delta gene and genomic probes, we have analyzed T cell receptor (TCR) delta gene rearrangement in 19 patients with T cell acute lymphoblastic leukemia (T-ALL) and 29 patients with B-precursor ALL. Five out of seven CD3- T-ALL and 4 of 12 CD3+ T-ALL showed bi-allelic rearrangements of the TCR-delta gene. In three CD3+ patients, a single allelic TCR-delta gene rearrangement was observed with rearrangement of the TCR-alpha gene on the other allele.

The isolation of the human delta chain gene and its expression in normal T cells and T cell leukemias.

In this paper we describe a gene that lies 85 kb 5' of the constant region of the human alpha chain and some 30-50 kb 3' of the alpha chain V region (H. Griesser, unpublished observation). This gene undergoes somatic recombination and is transcribed in thymocytes, PHA-stimulated peripheral blood T cells, and some T cell leukemic cell lines.

Sequence and organization of the diversity, joining, and constant region genes of the human T-cell delta-chain locus.

In this paper we describe the genomic organization and sequence of the human T-cell receptor delta-chain diversity, joining, and constant genes. There is one delta-chain constant region gene (C delta) located approximately equal to 85 kilobases (kb) upstream of the alpha-chain constant region. The delta-chain constant region consists of four exons, whose organization is very similar to that of the C alpha exons, suggesting that C alpha and C delta may have arisen from a gene duplication event.

Segregation of precursors with high proliferative potential from their differentiated progeny in a myeloma cell line.

Human myeloma colonies were grown from the peripheral blood of a patient with multiple myeloma who was unresponsive to any further therapy. The majority of primary myeloma colonies contained cells that were able to form secondary colonies upon replating and facilitated the establishment of a myeloma cell line (OCI-My5). The recloning procedure was repeated for colonies that contained the highest and lowest number of clonogenic progenitors.

Hemopoietic colony growth-promoting activities in the plasma of bone marrow transplant recipients.

Plasma samples were obtained from 34 bone marrow transplant (BMT) recipients before and after administration of the preparative regimen and tested for their ability to promote and/or support growth of hemopoietic colonies. The ability of plasma samples to promote colony formation on their own was tested on normal nonadherent target cells without addition of exogenous growth factors. The growth-supporting activity was examined in the presence of medium conditioned by phytohemagglutinin-stimulated leukocytes (PHA-LCM) and/or erythropoietin (EPO).

Rearrangement of T-cell delta locus in lymphoproliferative disorders.

Studies of lymphoproliferative disorders using immunoglobulin and T-cell receptor genes have contributed to our understanding of clonality and lineages of these disorders. In this study, we examined the rearrangement of the recently discovered T-cell delta chain genes in a variety of lymphoproliferative diseases. We show here that six of 14 T-cell lymphomas and five of 23 B-cell lymphomas or B-cell leukemia cell lines have rearranged the delta loci, while two of two hyperimmune reactions retain germline configuration within these genes.

Structure and rearrangement of the T cell receptor J alpha locus in T cells and leukemic T cell lines.

The vast majority of T cells express an antigen receptor (TcR) composed of an alpha/beta heterodimer. The alpha and beta chains are encoded for by a set of variable (V), joining (J) and constant (C) region genes. Unlike the J genes of the beta chain which are limited in number and are clustered close to the constant region, the J alpha genes are spread over an 85-kilobase DNA region, upstream of the C alpha gene.

The effects of combinations of the recombinant growth factors GM-CSF, G-CSF, IL-3, and CSF-1 on leukemic blast cells in suspension culture.

The blast cells of acute myeloblastic leukemia may be considered as a renewal population maintained by stem cells that are capable of both self-renewal and differentiation. Blast stem cells grow in culture usually when stimulated by growth factors normally active on myelopoietic cells. Two culture methods permit an evaluation of the balance between self-renewal and differentiation; previous studies have shown that this balance can be affected by recombinant growth factors.

The effects of recombinant CSF-1 on the blast cells of acute myeloblastic leukemia in suspension culture.

Recombinant hemopoietic colony-stimulating factors (CSFs), including GM-CSF, G-CSF and IL-3, have been shown to be effective stimulators of both self-renewal and terminal differentiation of blast stem cells in acute myeloblastic leukemia (AML). We have examined the activity of a fourth growth factor, recombinant CSF-1 (or M-CSF), on the growth of leukemic blasts in culture. CSF-1 was found to be active on some, but not all, blast populations.

Expression of the CSF-1 gene in the blast cells of acute myeloblastic leukemia: association with reduced growth capacity.

Myelopoietic growth factors are known to influence the growth in culture of malignant blast cells from human Acute Myeloblastic Leukemia (AML). We have used cDNA clones for the factor CSF-1 and its receptor fms to study DNA and RNA from the blasts of 25 AML patients. The CSF-1 gene was always in the germline configuration.

Comparison of T cell receptor alpha, beta, and gamma gene rearrangement and expression in T cell acute lymphoblastic leukemia.

We have analyzed the configuration of the T cell receptor (TCR) alpha gene using newly developed genomic joining region (J alpha) probes, which cover approximately 80 kb of the J alpha region upstream from the constant region in 19 patients with T cell acute lymphoblastic leukemia (T-ALL) and in three CD3- leukemic T cell lines (HSB2, CEM, and MOLT4). In parallel, transcription of the TCR-alpha, beta, and gamma genes was examined in 11 of these patients and in the T cell lines. All T-ALL and the three T cell lines exhibited both TCR-gamma and beta gene rearrangements.

The human T cell receptor alpha-delta locus: a physical map of the variable, joining and constant region genes.

In this study a physical macro-restriction map of the entire human alpha locus that spans about 1000 kilobase pairs and includes the V alpha, J alpha and C alpha genes is presented. Evidence is provided that gene duplications were involved in the increase of genomic diversity of V alpha genes. In addition, we show a detailed map of a 40-kb region located approximately 100 kg upstream of the human C alpha gene.

Binding of iodinated recombinant human GM-CSF to the blast cells of acute myeloblastic leukemia.

Granulocyte/macrophage-colony-stimulating factor (GM-CSF) is an effective growth factor for the blasts of acute myeloblastic leukemia (AML). Radioiodinated Chinese hamster ovary (CHO)-cell derived GM-CSF was prepared using Bolton-Hunter reagent to label free amino groups on the protein. Normal human neutrophils and the blast cells from AML patients were examined for binding.

Sequence and organization of the human T cell delta chain gene.

A novel human T cell receptor (TcR) gene, located 85 kbp upstream to the C alpha coding regions, was isolated using human genomic clones to identify cDNA homologous to messages encoded by this region. The deduced protein sequence of this gene is highly homologous to that of the newly identified constant region found in the murine TcR alpha chain locus. This gene undergoes rearrangements and is expressed at the RNA level in human thymocytes, peripheral T cells and several leukemic T cell lines which have been shown to express the surface gamma-delta heterodimer, suggesting that this gene encodes the human T cell delta chain.

Structure and expression of genes of GM-CSF and G-CSF in blast cells from patients with acute myeloblastic leukemia.

The hematopoietic growth factors granulocyte/macrophage colony-stimulating factor (GM-CSF) and G-CSF, available as recombinant products, stimulate the growth in culture of blasts from patients with acute myeloblastic leukemia (AML). We used cDNA probes for each gene to study the genomic organization in blast cells of 22 patients and expression in the blast cells of 18 patients. Alteration in the structure of G-CSF (two instances) and GM-CSF (two instances) was found.

Magnetic resonance imaging for monitoring relapse of acute myeloid leukemia.

Magnetic resonance provides a non-invasive tool for monitoring normal and leukemic bone marrow. Measurements of the T1 relaxation times are elevated in acute myelogenous leukemia. However, interpatient variability diminishes the usefulness of MR measurements for diagnosing leukemia.

Stem cell renewal and differentiation in acute myeloblastic leukaemia.

The defining properties of stem cells are capacities for self-renewal and, after determination, a limited number of terminal divisions. The blast cells of acute myeloblastic leukaemia (AML) are maintained by stem cells with these two properties. Since renewal and differentiation can be assessed separately in cultures of AML blasts, these cancer cells provide a useful model for examining stem regulation; such studies have practical importance for future developments in the treatment of AML.

Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation.

In a retrospective analysis (July 1979 to March 1984) of 120 allogeneic adult bone marrow transplant recipients, we identified seven patients with small-airway disease for whom no microbiologic agent was detected. Six had pulmonary function studies demonstrating air flow obstruction. Five of the seven patients had an open-lung biopsy showing pathologic changes within small airways; these varied from early bronchiolar wall damage to bronchiolitis obliterans.

Clonogenic hemopoietic precursors in bone marrow transplantation.

Multilineage and single-lineage hemopoietic precursors were studied in 102 bone marrow transplant recipients and their respective donors to determine their contribution to clinical outcome as measured by time to engraftment and survival. The patient population was heterogenous with respect to diagnosis and disease status. They included individuals with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), aplastic anemia, and a few other hematopoietic malignancies.

Growth of human hemopoietic colonies in response to recombinant gibbon interleukin 3: comparison with human recombinant granulocyte and granulocyte-macrophage colony-stimulating factor.

Supernatants of COS-1 cells transfected with gibbon cDNA encoding interleukin 3 (IL-3) with homology to sequences for human IL-3 were tested for ability to promote growth of various human hemopoietic progenitors. The effect of these supernatants as a source of recombinant IL-3 was compared to that of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) as well as to that of medium conditioned by phytohemagglutinin-stimulated leukocytes. The frequency of multilineage colonies, erythroid bursts, and megakaryocyte colonies in cultures containing the COS-1 cell supernatant was equivalent to the frequency observed in the controls and significantly higher than found in cultures plated with recombinant GM-CSF.

Small-airways disease in recipients of allogeneic bone marrow transplants. An analysis of 11 cases and a review of the literature.

In a retrospective review of 116 consecutive allogeneic bone marrow transplants (BMT), severe obstructive airways disease was identified in 11 patients. Lung pathology demonstrated bronchiolitis in 9 patients and physiologic studies showed small-airways disease consistent with bronchiolitis in the other 2. None of the 5 patients with associated infection survived, while 3 of the 6 patients without an identified pathogen stabilized or improved.

The effects of three recombinant growth factors, IL-3, GM-CSF, and G-CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture.

The blast stem cells of acute myeloblastic leukemia (AML) respond in cell culture to growth factors by both self-renewal and terminal divisions. Both of these functions have been shown to be stimulated by the recombinant growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). In this paper, recombinant gibbon interleukin-3 (IL-3), homologous to human IL-3, was tested on blast cells and compared with the effects of GM-CSF, G-CSF, and medium conditioned by the bladder cell line 5637 (5637-CM).