Immunological (surface-marker) tests have been used to define four subgroups of acute lymphoblastic leukaemia (A.L.L.) in childhood: T-A.L.L., B-A.L.L., common-A.L.L., and null-A.L.L. A study of 94 children shows that the common-A.L.L. subgroup achieves a much longer duration of remission than T-A.L.L.; our findings also confirm the association of some clinical features with T-cell A.L.L. Within the common-A.L.L. subgroup, initial white-cell count correlates with prognosis.

Adolescent↗

PubMedDate not supplied

The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus.

Acquired immune deficiency syndrome (AIDS) is characterized by opportunistic infections and by 'opportunistic neoplasms' (for example, Kaposi's sarcoma). Persistent generalized lymphadenopathy (PGL) is epidemiologically associated with AIDS, especially in male homosexuals. A subset of T lymphocytes positive for the CD4 antigen (also termed T4 antigen), is depleted in AIDS and PGL patients. A retrovirus found in T-cell cultures from these patients is strongly implicated in the aetiology of AIDS because of the high frequency of isolation and the prevalence of specific antibodies in the patients. Here we have detected cell-surface receptors for the AIDS retrovirus (human T-cell leukaemia virus-III (HTLV-III) and lymphadenopathy-associated virus-1 (LAV-1) isolates) by testing the susceptibility of cells to infection with pseudotypes of vesicular stomatitis virus bearing retroviral envelope antigens, and by the formation of multinucleated syncytia on mixing virus-producing cells with receptor-bearing cells. Receptors were present only on cells expressing CD4 antigen; among 155 monoclonal antibodies tested, each of the 14 anti-CD4 antibodies inhibited formation of syncytia and blocked pseudotypes. Productive infection of CD4+ cells with HTLV-III or LAV-1 markedly reduced cell-surface expression of CD4. In contrast, receptors for HTLV-I and HTLV-II were not restricted to CD4+ cells, were not blocked by anti-CD4 antibodies; cells productively infected with HTLV-I and HTLV-II expressed surface CD4. Hence, we conclude that the CD4 antigen is an essential and specific component of the receptor for the causative agent of AIDS.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia.

The Philadelphia (Ph) chromosome breakpoints in chronic myelocytic leukaemia are clustered on chromosome 22 band q11 in a 5.8-kilobase (kb) region designated bcr. The c-abl protooncogene is translocated from chromosome 9 band q34 into bcr and the biochemical consequence of this molecular rearrangement is the production of an abnormal fusion protein bcr-abl p210 with enhanced protein-tyrosine kinase activity compared to the normal p145 c-abl protein. The Ph chromosome translocation is also seen in some acute lymphoblastic leukaemias with B-cell precursor phenotypes some of which have bcr rearrangement (bcr+) and some do not (bcr-). We present evidence that the Ph+, bcr- leukaemias are associated with a novel p190 abl kinase. We propose that acute lymphoblastic leukaemias that are bcr+, p210+ are probably lymphoid blast crises following a clinically silent chronic phase of chronic myelocytic leukaemia arising in multipotential stem cells whereas bcr-, p190+ cases are de novo acute lymphoblastic leukaemias arising in more restricted precursors.

Adolescent↗

PubMedDate not supplied

Compartmentalization of a haematopoietic growth factor (GM-CSF) by glycosaminoglycans in the bone marrow microenvironment.

Haematopoietic progenitor cells proliferate and mature in semisolid media when stimulated by exogenous haematopoietic cell growth factors (HCGFs) such as granulocyte-macrophage colony-stimulating factor (GM-CSF). They also proliferate in association with marrow-derived stromal cells although biologically active amounts of HCGFs cannot be detected in stromal culture supernatants. It is possible that HCGFs are synthesized in small amounts by stromal cells but remain bound to the stromal cells and/or their extracellular matrix (ECM). This interpretation accords with haematopoietic progenitor cell proliferation in close association with stromal layers in long-term cultures. Glycosaminoglycans (GAGs) are found in the ECM produced by stromal cells. They are prime candidates for selectively retaining HCGFs in the stromal layer; they influence embryonic morphogenesis and cyto-differentiation and they may regulate haematopoiesis. We now report that granulocyte-macrophage colony-stimulating activity can be eluted from cultured stromal layers and that exogenous GM-CSF binds to GAGs from bone marrow stromal ECM. Selective compartmentalization of HCGFs in this manner may be an important function of the marrow microenvironment and may be involved in haematopoietic cell regulation.

Animals↗

PubMedDate not supplied

Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia.

Normal haematopoietic cell regulation involves interaction between marrow stromal cells and haematopoietic progenitor cells which may be facilitated by specific recognition and adhesion. Some leukaemogenic events might produce a selective growth advantage by altering this regulatory network, possibly by diminishing the capacities of cells to adhere to stromal elements. Using an in vitro culture system which allows investigation of adhesion to stromal layers and subsequent colony formation by blast colony-forming cells (B1-CFC) in normal marrow and Ph+ chronic myeloid leukaemic (CML) blood, we compared the adhesive properties of normal and malignant progenitor cells. We present evidence that altered adhesive interactions between primitive progenitor cells and marrow stromal cells occur in CML.

Bone Marrow↗

PubMedDate not supplied

High performance for expert systems: I. Escaping from the demonstrator class.

An investigation was performed to elucidate the problems of converting a demonstrator expert system for leukaemia diagnosis into a large high-performance system. Analysis of the logical completeness of the demonstrator system revealed only minor errors and a limited representation of the domain. Most of its test cases were quite simple and correction of the minor errors raised the performance to 94%. However, the remaining cases were very complex and it is doubtful whether the system could handle them without fundamental changes to its representation of the domain. Demonstrator systems can function with an imperfect view of the domain since the small sacrifice of accuracy is of little consequence; but in a high-performance system the imperfections must be corrected before extra detail is added. The use of default mechanisms for making specific conclusions was harmful because they concealed errors, and a numerical method for handling uncertainty contributed nothing of value to the system.

Diagnosis, Computer-Assisted↗

PubMedDate not supplied

High performance for expert systems: II. A system for leukaemia diagnosis.

A system for diagnosing leukaemia subtypes from monoclonal antibody test results has been programmed directly from the expertise of one immunologist. It gives an acceptable conclusion for 400 past cases, with summaries of its reasoning and suggestions for further tests. Its development included three major components: elicitation of the basic items of knowledge, formulation of a coordinated overall scheme, and representation in a computer language. All three were interdependent and required many cycles of trial and error, involving further discussions with the expert at all stages. By far the most difficult component was the formulation of a comprehensive specification for the problems of the domain, and this was only achieved when the knowledge engineer had gained a fair understanding of the application. The system is a tree-structured logic program written in PROLOG. This format facilitated experimentation with different knowledge representations, control of the interrelationships between rules and the elimination of errors. The problems of quality control and maintenance are of paramount importance for high-performance systems.

Diagnosis, Computer-Assisted↗