Arthur K. Sullivan

Small lymphocyte T‐cell leukemia in the adult

A 49‐year‐old man is described with morphologic T cell chronic lymphocytic leukemia, whose clinical course, however, progressively deteriorated with central nervous system involvement, resistance to treatment and death within eight months. In addition to widespread organ invasion by leukemic cells there was depression of cellular immunity. The leukemic lymphocytes showed an aberrant response to mitogens, and despite undetectable Ia‐like surface antigens were able to stimulate allogeneic cells in the mixed leucocyte reaction. From this and similar cases reviewed herein, it appears that the syndrome of small T‐lymphocyte leukemia of the adult is a rapidly aggressive and resistant disease with characteristic clinical and laboratory findings. Cancer 42:2920–2927, 1978.

Characterization of an acquired IgG inhibitor of coagulation factor XIII in a patient with systemic lupus erythematosus

An acquired IgG inhibitor to factor XIII was identified in a 30‐year‐old Vietnamese woman with systemic lupus erythematosus. The IgG fraction was isolated from plasma by chromatography on an agarose gel column and by protein G adsorption. The anti‐factor XIII activity, identified within the IgG fraction, inhibited factor XIII from both normal plasma (a2b2) and platelets (a2). A normal level of the b subunit was measured by immunoelectrophoresis of the patient’s plasma, but the a subunit was not detected. These results suggested the presence of an IgG immunoglobulin which recognized the a subunit and interfered with its activity.

Deficiency of neutrophilic granule membrane glycoproteins in the myelodysplastic syndromes: A common deficiency in 216 patients studied by the cancer and leukemia group B

Previous studies on neutrophils in patients with the myelodysplastic syndromes (MDS) have indicated deficiencies in the contents of primary and secondary granules. However, the granule membrane remains virtually unstudied despite its essential role in the dynamic function of the cytoplasmic granules. In this study, we examined the membrane glycoproteins of primary and secondary granules of peripheral blood and/or bone marrow neutrophils using the monoclonal antibody H36/71 to CD15 glycoproteins. In addition, myeloperoxidase activity and antigen, elastase and lactoferrin were also studied using cytochemical and immunocytochemical stains. A total of 216 patients were included. Deficiencies of granule membrane glycoproteins were the most common, detected in 49%, followed by myeloperoxidase activity (17%), elastase (16%), myeloperoxidase antigen (9%), and lactoferrin (8%). Multiple deficiencies always included granule membrane deficiency. We conclude that granule membrane defects are common in MDS, may provide a common mechanism for multiple granule deficiencies, and may prove to be an additional abnormality associated with granulocyte dysfunction.

Augmentation of human natural cytotoxic cell activity by leukotriene B4 mediated by enhanced effector-target cell binding and increased lytic efficiency☆

The addition of leukotriene B4 (LTB4) to cytotoxicity assays measuring natural killer (NK) or natural cytotoxic (NC) cell activities resulted in significantly augmented killing of K562 or herpes simplex virus (HSV)-infected target cells, respectively. Since the mechanism of cytotoxicity implies several steps, including the binding of effectors to targets which is Mg2+-dependent and the programming of lysis of the target which is Ca2+-dependent, we undertook to define the step(s) at which LTB4 acted in augmenting cytotoxicity. Our results showed that LTB4 significantly increased the percentage of effector-target conjugates when K562- or HSV-infected targets were incubated with lymphocytes. Maximal binding occurred at a concentration of LTB4 of 1 X 10(-10) M. Preincubation of lymphocytes and not target cells with LTB4 was sufficient to observe the increased binding. PBML binding to and killing of the NK-resistant target clone I, derived from K562, was not enhanced by LTB4. In the absence of Ca2+, cytotoxicity was impaired and LTB4 could not restore it. Use of a single cell lytic assay demonstrated augmented efficiency of lysis of both K562 and HSV-infected targets in the presence of LTB4. These findings suggest that LTB4 may augment natural cytotoxicity by enhancing target cell recognition by cytotoxic effector cells and subsequently by augmenting their lytic efficiency.

Loss of promyelocytic maturation in HL60 sublines: a potential model for leukaemia progression

The majority of cells of the human leukaemic line HL60 appear to be promyelocytes which can be stimulated to mature into functioning neutrophils. We report here the derivation of stable subclones from the parent line which differ. Two forms of variant were obtained: (1) those with a defined lesion, selected by resistance to kill by 6‐thioguanine, which matured in the presence of DMSO and retinoic acid but not in hypoxanthine. They also continued to express peroxidase and a major granulocyte antigen, and (2) those obtained by clonal growth in DMSO which did not mature in the presence of any compound tested including hypoxanthine, DMSO, retinoic acid and actinomycin D and lacked granules, peroxidase and the granulocyte antigen. The concurrent loss of the characteristic of maturability and the phenotype of myeloid commitment suggests that the control of the two phenomena may be related. These variant cell lines provide a useful model in which to study how human leukaemic cells may become arrested in less differentiated stages of development.

Target cell specificity of human natural killer (NK) cells: I. Development of an NK-resistant subline of K562

By depletion of effector-target conjugates and cloning, a variant of the human leukemic line K562 that is partially resistant to lysis by natural killer (NK) cells when tested under conditions of culture and assay identical to that of the parent has been derived. Its karyotype shows markers similar to the original K562. The resistant phenotype remains stable after over 1 year of continuous passage and persists in multiple replicate subclones. However, it can be killed to a degree equal to the parent by antibody-activated complement, antibody-dependent cellular mechanisms, and by effector cells activated by staphylococcal protein A. These observations and experiments on cold target competition suggest that on its surface there is a significantly decreased, absent, or blocked effective target structure for a major population of unstimulated peripheral blood NK cells.

Psychiatric assessment of candidates for bone marrow transplantation: a psychodynamically-oriented approach.

Objective: To seek possible relationships between psychological factors and survival after an intensive medical therapy, using bone marrow transplantation as a model. Method: Candidates for bone marrow transplantation underwent two to three psychodynamically-oriented psychiatric interviews that explored family functioning (“F”), individual psychological maturity (“I”), and the capacity to form and communicate a mature psychological construct of the transplant (“T”) process. The results were recorded in a semi-quantitative manner, assigning a possible score of 1 to 3 for each parameter, for a possible total of 3 to 9 (the “F.I.T.” assessment). Survival after the transplant was analyzed retrospectively in relation to the F.I.T. assessment. Results: In a series of 112 candidates interviewed prior to transplant, those with the lowest F.I.T. assessment tended not to survive as long. By one year, 95 percent of individuals assigned the lowest score (F.I.T. = 3) had died, whereas 96 percent of those assigned the highest scores (F.I.T. = 7–9) remained alive. The strongest predictors were the “I” and “T” parameters. Conclusion: This approach to assessment of candidates for bone marrow transplantation may identify individuals who require added supportive measures, both medical and psychological. Furthermore, the results suggest possible leads in the search for how psychological factors might influence the physiologic response to a toxic stress.

Double Esterase Staining andOther Neutrophilic Granule Abnormalities in 237 Patients with the Myelodysplastic Syndrome Studied by the Cancer and Leukemia Group B

We investigated double (specific and nonspecific) esterase (DE) staining in marrow cells of 237 patients with the myelodysplastic syndromes (MDS). Additional abnormalities of neutrophilic granules were examined cytochemically and immunocytochemically for myeloperoxidase activity and antigen elastase, lactoferrin and CD15 granule-membrane glycoproteins. Abnormal DE staining (≥3% of all nucleated marrow cells) was present in 27% of patients with no difference among different MDS subtypes. However, the prevalence of high abnormal DE staining (≥10%) was significantly lower in refractory anemia with excess blasts in transformation (1%) compared to other MDS subtypes (12–15%; p = 0.004). The prevalence of other granule abnormalities was not statistically different in the DE normal and DE abnormal groups. Abnormal DE staining is relatively common among all MDS subtypes. High DE staining may identify a subgroup of patients with a lower grade MDS.

Antigens differentially expressed on surface and cytoplasmic structures of human myeloid cells.

Specialized internal granules are a major feature of myeloid differentiation and are deficient in most acute myeloid leukemia cells. Although they arise from the same synthetic apparatus as does the plasma membrane, their relationship to it is not well characterized in human tissues. Using murine monoclonal antibodies, we have identified myeloid-related structures that illustrate three possible modes of antigen expression in these organelles. Immunocytochemical studies with the light microscope have shown that the first (D51) was restricted to the surface of neutrophils, monocytes, megakaryocytes and platelets; a second (D46) was found on the surface of blastic cell lines but on only internal components of mature granulocytes; the third (H36/71) appeared on both the surface and internal particles of promyelocytes, myelocytes and polymorphs. These model antigens may be used to study the control of granule synthesis in normal and leukemic cells.

Expression of a B-lymphocyte antigen in chronic lymphocytic and other leukemias

Abstract A major plasma membrane glycoprotein of molecular weight 32,000–36,000 was isolated from cultured human B lymphoblasts. Its molecular, antigenic, and functional properties established a relationship to the human Ia equivalent. Monospecific antisera to this protein reacted with lymphocytes from 11 patients with chronic lymphocytic leukemia (CLL) of the B-cell type as expected. However, in serial studies of three additional CLL patients, the circulating levels of antigen-bearing cells fluctuated markedly with time. Furthermore, expression of the antigen was dissociated from that of surface immunoglobulin, especially during periods of rapid change in leukocyte count. Blast cells from patients with acute myeloblastic, acute myelomonocytic, and acute lymphoblastic (E rosette-negative) leukemias expressed it as well. Leukemic cells containing the Philadelphia chromosome from a patient with chronic granulocytic leukemia in a blastic phase also carried the antigen. Although Ia-like antigens in man are characteristically expressed on B lymphocytes, they are not specific for them, but may serve a more general function as differentiation antigens on some hematopoietic cell precursors.