An increasing number of reports document instances in which individual leukemic cells coexpress markers normally believed to be restricted to a single lineage. This has been interpreted by McCulloch and colleagues as aberrant programming or lineage infidelity and contrasts with earlier suggestions that lineage fidelity of gene expression was usually maintained in leukemia. We argue that several examples of infidelity are suspect on technical grounds, whereas others are bona fide and require explanation, eg, partial rearrangements and expression of Ig heavy-chain and/or T cell receptor genes in inappropriate cells and terminal deoxynucleotidyl transferase in leukemic myeloblasts. Individual examples of truly aberrant gene expression may well occur in leukemia but with insufficient regularity to be of general significance. We suggest that verifiable and consistent examples of apparent lineage infidelity do not reflect genetic misprogramming but rather the existence of a transient phase of limited promiscuity of gene expression occurring in normal biopotential or multipotential progenitors and able to be preserved as a relic in leukemic blast cell populations that are in maturation arrest. This alternative explanation has interesting implications for mechanisms of hematopoietic differentiation and leads to some testable predictions.

T gamma lymphocytes are those lymphocytes that express receptors for both the Fc portion of IgG and sheep erythrocytes. A very high proportion of normal T gamma lymphocytes are large granular lymphocytes (LGL), the cell responsible for most, if not all, natural killer (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC) in humans, rats, and mice. In general, these cells are large lymphocytes with prominent azurophilic granules in the cytoplasm. Recently, a group of lymphoproliferative disorders made up predominantly of T gamma lymphocytes has been described. The most common and best studied of these disorders we refer to as "chronic T gamma-lymphoproliferative disease" (T gamma-LPD). In most cases, this disease represents the abnormal expansion of LGL, which is reflected by an increase in functionally active NK or ADCC effector cells. The chronic T gamma-LPD lymphocytes are generally characterized as E- and EA-rosette positive, acid-phosphatase, and beta-glucuronidase positive and express the pan-T antigens OKT3/Leu-4, OKT11/Leu-5, the suppressor-associated antigens OKT5,8/Leu-2, and the NK-associated antigens Leu-7/HNK-1. Typically, the patients are older, predominantly males and characteristically have a lymphocytosis of predominantly T gamma lymphocytes with lymphocyte infiltration of the bone marrow and often the spleen. While chronic T gamma-LPD is not usually an aggressive disease, the patients are often neutropenic and have recurrent bacterial infections requiring antibiotic therapy. Some patients have benefited from cytotoxic chemotherapy., but most patients have not required chemotherapy. An experimental LGL leukemia in F344 rats appears morphologically, functionally, and clinically similar to the human chronic T gamma-LPD and serves as an experimental model for further examining the ontogeny and function of LGL and may be applicable for exploring new and more effective means for the treatment of patients with chronic T gamma-LPD.

Prenatal diagnosis of hematologic diseases can now be performed with fetal blood, fetal amniotic fluid cell DNA, and fetal chorionic villi DNA. Some hemoglobinopathies can be detected by all three methods, and the choice will depend on the available obstetric and laboratory techniques, as well as the time of presentation of the pregnancy. Hopefully, further development of molecular probes and techniques will soon expand these options to all of the globin disorders. Detection of coagulation disorders in utero currently requires samples of pure fetal blood. Gene cloning is accomplished for some (factor IX and antithrombin III) and is underway for others (factor VIII), and further investigation is necessary to determine whether deficiencies in these gene products are due to gene deletion or to mutant genes linked to polymorphic restriction enzyme sites of diagnostic use. Thus, molecular biology may be applied to prenatal diagnosis of the clotting problems, but this has not yet been accomplished. Disorders affecting the number and/or function of erythrocytes, leukocytes, and platelets can be diagnosed by analysis of fetal blood. Blood samples will continue to be required until more is known about the molecular biology of hematopoiesis. Syndromes that can be diagnosed by chromosome studies should be revealed in cultures of amniotic fluid cells, fetal blood lymphocytes, and chorionic villi cells. Cultured cells can be examined for karyotypes, Y-chromatin, spontaneous or induced chromosome breakage, DNA repair, SCEs, and translocations. The techniques for culturing amniotic cells and fetal blood white cells are established, and those for growing cells from chorionic villi are improving rapidly. Direct preparations of cells from villi only may suffice for some of the above analyses. The study of hematologic disease in utero has thus come full circle, from the use of amniotic cells to determine the sex in X-linked disorders, to fetal blood sampling for the analysis of gene products, then back to amniocentesis for DNA, and now earlier in gestation to chorionic villi. All of this has occurred in less than ten years, and it is anticipated that developments in the next ten years will be equally dramatic. The future should bring all prenatal testing into the first trimester, use molecular probes, and provide for both early diagnosis and early treatment of genetic hematologic disease.

Bleeding and thrombosis are major causes of morbidity and mortality in patients with myeloproliferative disorders. The significance of uncontrolled polycythemia as a risk factor for thrombosis in these patients has been established. However, the role of thrombocytosis in the pathogenesis of hemostatic complications remains controversial. Abnormalities of platelet function and prolongation of the bleeding time occur in a highly variable number of cases. Specific platelet defects that have been identified in the myeloproliferative defects include abnormal platelet morphology, acquired storage pool disease, platelet membrane abnormalities, and abnormal arachidonic acid metabolism. Causal relationships between any of these specific abnormalities and either bleeding or thrombosis have not been clearly established. The therapeutic efficacy of myelosuppression to reduce the platelet count in patients with thrombocytosis and the role of antiplatelet drugs in the myeloproliferative disorders are controversial issues.

Platelet activity may be involved in tumor metastasis. The tumor cells, after detachment from the primary site, adhere to vascular endothelium at distant sites and proliferate. Platelets form aggregates with tumor cells in circulation, facilitating their adhesion to the vascular endothelium. Formation of platelet-tumor cell aggregates and their sequestration in various end-organs may result in thrombocytopenia. Certain tumor cell lines directly stimulate platelet activity, some by releasing platelet-aggregating material, a urea-extractable membrane component, others by release of cathepsin, and still others by undefined mechanisms. The direct effect of platelets on tumor cells may be of pathogenic significance. For example, platelet-derived factors stimulate growth of some tumors, whereas others increase vascular permeability and thus facilitate migration of tumor cells across the vessel wall. Lack of these platelet factors, as in thrombocytopenic animals, may indeed inhibit tumor metastasis. Arachidonic acid metabolism in platelets and the vessel walls may contribute to metastatic process. In particular, thromboxane A2 and prostacyclin generation capabilities appear to be important in modulating platelet-tumor cell deposition and growth. To alter the metastatic process, several preliminary trials of platelet-inhibitory agents have been performed. However, the results of these trials have been equivocal, perhaps related to nonspecific effects of these agents on arachidonic acid metabolism. Studies directed at specific pathways of platelet-vessel wall interaction on some tumors appear promising. These newer agents may be of therapeutic value in man.

A prominent phenotypic abnormality of human acute myelogenous leukemia cells is the inability of the cells to differentiate to functional mature cells; instead, the cells are blocked at an early stage of development and remain in the proliferative pool and rapidly accumulate. Investigation of the induction of myeloid leukemic cell differentiation has made recent advances with the development of several human myelogenous leukemia cell lines. The lines provide models to study the biology of myeloid differentiation and to identify inducers of differentiation of myeloid leukemic blood cells. This review critically examines the inducers of leukemic cell differentiation and their potential therapeutic importance.