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Our understanding of leukemia development and progression has been hampered by the lack of in vivo models in which disease is initiated from primary human hematopoietic cells. We showed that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells (L-ICs) that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The L-ICs retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. The properties of these cells provide a biological basis for several clinical hallmarks of MLL leukemias.

Paraneoplastic pemphigus patients (PNP) develop a group of autoantibodies, among which those against envoplakin and periplakin are almost always found. Epitope mapping has indicated that the linker subdomains of the proteins harbor the major antigenic sites recognized by PNP sera. In order to detect specific autoantibodies for the diagnosis of PNP, we expressed recombinant proteins containing linker subdomains of human periplakin and envoplakin in a human kidney cell line, and used them as the antigens for ELISAs. We found that all of the sera from 16 PNP patients recognized these two recombinant proteins by ELISA, and sera from 20 pemphigus vulgaris (PV), 12 pemphigus foliaceus (PF), 20 bullous pemphigoid (BP), 2 Castleman's tumor without PNP and 20 normal controls showed negative results. We also expressed the extracellular domain of desmoglein 3 (Dsg3) in the cell line, and used this recombinant Dsg3 as the ELISA antigen. Only 11 of our 16 PNP sera were positive, and most PV sera were positive. Our findings indicate that ELISAs using the recombinant proteins containing linker subdomains of envoplakin and periplakin expressed in a human cell line as the antigens are highly sensitive and specific for the diagnosis of PNP.

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.

Ortmann, E. K., Mayerhofer, T., Getoff, N. and Kodym, R. Effect of Antioxidant Vitamins on Radiation-Induced Apoptosis in Cells of a Human Lymphoblastic Cell Line. Radiat. Res. 161, 48–55 (2004). Modulating the amount of radiation-induced apoptosis by administering antioxidant vitamins offers a possible way to influence radiation-induced side effects in normal tissues. Therefore, we investigated the effect of beta-carotene, vitamin C and alpha-tocopherol on radiation-induced apoptosis in cells in culture. Human T-lymphoblastic MOLT-3 cells were irradiated with a dose of 3 Gy 1 h after or immediately prior to the addition of vitamins in three concentrations (0.01 μM, 1 μM and 100 μM). Eight hours later, apoptosis was scored morphologically by staining the nuclear DNA with Hoechst 33342. When given prior to irradiation, beta-carotene and vitamin E reduced the amount of radiation-induced apoptosis significantly at concentrations of 0.01 μM and 1 μM. In contrast, vitamin C did not show any protective effect when given at these two concentrations and caused a slight but significant radiosensitization at 100 μM. At 0.01 μM, all combinations of two vitamins showed a protective effect. This was also observed for the combination of all three vitamins at concentrations of 0.01 and 1 μM. When given immediately after irradiation, each of the three vitamins showed a protective effect at 0.01 μM. In addition, the combination of alpha-tocopherol and vitamin C reduced radiation-induced apoptosis slightly when given at 1 μM. In all other cases, no statistically significant modulation of radiation-induced apoptosis was observed. In our experimental system, the protective effect of beta-carotene and vitamin E was dependent on concentration and occurred only in the micromolar and sub-micromolar concentration range, while vitamin C alone, but not in combinations, had a sensitizing effect, thus arguing for a careful consideration of vitamin concentrations in clinical settings.

The effects of X-rays on cell survival, apoptosis, and long-term response in the development of cell death as measured by the dye exclusion test were studied in human leukemic MOLT-4 cells (p53 wild-type) stably transfected with a mutant p53 cDNA expression vector. Cell survival, as determined from colony-forming ability, was increased in an expression level dependent manner, but the increase was partial even with the highest-expressing clone (B3). This contrasts with the prior observation that cell death and apoptosis in B3 are completely inhibited at 24 h after irradiation with 1.8 Gy of X-rays1). The examination of B3 cells incubated for longer than 24 h after X-irradiation showed a delay in the induction of cell death and apoptosis. Western blot analysis revealed that the time required to reach the highest level of wild-type p53 protein in B3 was longer than the time in MOLT-4 and that the p53 may be stabilized by the phosphorylation at Ser-15. These results suggest that the introduction of mutant p53 into MOLT-4 merely delays the development of apoptosis, during which the cells could repair the damage induced by X-rays, and results in the partial increase in cell survival.

In the present study the migration of human monocytes towards the supernatants of five different human myeloid leukemic cell lines, four different human lymphatic leukemic cell lines and blasts derived from three different patients with acute myeloid leukemia (AML) was studied and the role of monocyte chemoattractant protein (MCP)-1 was established with an ELISA assay. Large differences in migration of monocytes towards the leukemic cell supernatants were shown (variation of approximately 10 to 150% compared to positive control), but high amounts of monocyte migration was always restricted to myeloid leukemic cells (cell lines or patient blasts). MCP-1 turned out to play a major role in the migration, firstly since there was a direct correlation between the amount of migration and the concentration of MCP-1 in the supernatants, and secondly since the addition of anti-hMCP-1 was able to inhibit migration to background level in all cases. Cytotoxicity experiments with a MTT test using MCP-1-stimulated monocytes against two human myeloid leukemic cell lines showed no increase in cell death compared to unstimulated monocytes. It is concluded that monocyte migration towards leukemic cells is restricted to the myeloid lineage and is regulated by MCP-1, which is produced in different amounts by the leukemic cells. Besides, MCP-1 does not increase the direct toxic effects of monocytes on leukemic cells.

A retrospective analysis of the medical records of 86 children in prolonged remission from acute lymphoblastic leukaemia was performed to calculate changes in the rate of increase in height and weight gain. The rate of increase in height decreased during initial treatment, and the potential for final adult height was not regained. Weight gain was excessive; this started during treatment and persisted into the remission years. Values of weight adjusted for height did not return to values found before treatment until eight years after diagnosis. Several factors can account for this weight gain, but there is a practical need to provide dietary advice, particularly when chemotherapy is stopped.

We have assessed testicular function with luteinising hormone-releasing hormone (LH-RH) and human chorionic gonadotrophin stimulation tests in 44 boys previously treated with, or currently receiving, chemotherapy for acute lymphoblastic leukaemia (ALL). At the same time a testicular biopsy was performed in each boy and the morphology was studied. Histologically the chemotherapy appeared to damage the tubular system in particular, and the degree of damage was assessed by estimating the tubular fertility (TF) index which is defined as the percentage of seminiferous tubules containing identifiable spermatogonia. The mean TF index in all 44 biopsies was 51%. Only 2 of the 44 boys showed an absent or blunted testosterone response to human chorionic gonadotrophin. This suggests that Leydig cell function is rarely impaired by such chemotherapy and that most of the boys, similarly treat for ALL, will undergo normal pubertal maturation. Apart from the basal luteinising hormone (LH) levels in the prepubertal group which could not be compared, the median basal serum follicle-stimulating hormone (FSH), LH, and testosterone concentrations, the median peak FSH and LH responses to LH-RH, and the mean plasma testosterone responses to human chorionic gonadotrophin stimulation did not differ between the prepubertal, early pubertal, and late pubertal groups compared with normal boys of similar pubertal maturation. Three of 32 prepubertal ALL boys, and 5 of 12 pubertal ALL boys showed abnormalities of gonadotrophin secretion. The increased frequency of abnormalities of FSH secretion in the pubertal ALL boys compared with the prepubertal ALL boys could not be explained by more severe tubular damage in the former group. We conclude that moderately severe damage to the tubular system of the testis unassociated with Leydig cell impairment may not be detected in the prepubertal boy with current tests of testicular function.

Growth and hypothalamic-pituitary function have been studied in children in long-term remission from acute lymphoblastic leukaemia (ALL). All 14 children are growing and developing normally; in the 8 children in whom the hypothalamic pituitary axis was investigated endocrine function is normal. Continuing long-term review of these children is essential, but hypothalamic-pituitary investigation is required only when there is a decrease in growth velocity or delay in the onset of puberty.

Extracts of peripheral lymphocytes from six individuals with chronic lymphocytic leukemia (CLL) were assayed for the ability to remove O6-methylguanine (O6MeGua) from exogenous DNA. The O6MeGua-removing activity in CLL lymphocytes, predominantly B cells, was approximately 7-fold higher than in B lymphocytes of normal individuals and about 2-fold higher than in the unstimulated T type cells of normal persons. The activity measured in extracts of lymphocytes from three blood relatives was in the upper range of the normal distribution. Over 80% of the removal of O6MeGua was accomplished by the transfer of the methyl group to cysteine moieties of acceptor proteins in a stoichiometric reaction. If one assumes one acceptor group per acceptor protein, the calculated number of acceptor molecules per CLL lymphocyte falls between 91,000 and 220,000. Thus CLL lymphocytes do not show lower O6MeGua-removing activity, in contrast to many tumor cell strains or transformed cell lines, which are reported to have a deficient methyl excision repair phenotype (Mer-). Instead, the CLL lymphocytes act as if they have a super-Mer+ phenotype.