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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A chromosomal translocation in a T-cell leukemia involving the short arm of human chromosome 11 at band 11p15 disrupts the rhombotin gene. This gene encodes a protein with duplicated cysteine-rich regions called LIM domains, which show homology to zinc-binding proteins and to iron-sulfur centers of ferredoxins. Two homologues of the rhombotin gene have now been isolated. One of these, designated Rhom-2, is located on human chromosome 11 at band 11p13, where a cluster of T-cell leukemia-specific translocations occur; all translocation breakpoints at 11p13 are upstream of the Rhom-2 gene. Human and mouse Rhom-2 are highly conserved and, like rhombotin, encode two tandem cysteine-rich LIM domains. Rhom-2 mRNA is expressed in early mouse development in central nervous system, lung, kidney, liver, and spleen but only very low levels occur in thymus. The other gene, designated Rhom-3, is not on chromosome 11 but also retains homology to the LIM domain of rhombotin. Since the Rhom-2 gene is such a common site of chromosomal damage in T-cell tumors, the consistency of translocations near the rhombotin gene was further examined. A second translocation adjacent to rhombotin was found and at the same position as in the previous example. Therefore, chromosome bands 11p15 (rhombotin) and 11p13 (Rhom-2) are consistent sites of chromosome translocation in T-cell leukemia, with the 11p15 target more rarely involved. The results define the rhombotin gene family as a class of T-cell oncogenes with duplicated cysteine-rich LIM domains.
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PMID:The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. 203 76

The role of macrophages (M phi) in natural anti-chondrocyte cytotoxic activity of normal murine splenocytes (SPL) and peritoneal cells (PC) was examined by means of an 18-hr 51Cr-release assay. Removal of M phi by either plastic adherence or carbonyl iron and magnet resulted in significant (P less than 0.01) reduction of SPL-mediated lysis of chondrocytes. It, however, did not influence natural anti-YAC-1 leukemia activity. On the contrary, M phi-depleted suspensions of PC retained their anti-chondrocyte activity at the initial level. Neither adherent SPL nor adherent PC exerted significant anti-chondrocyte cytotoxicity. The activity of nonadherent SPL could be, however, restored by reconstitution with the graded numbers of syngeneic adherent spleen- or peritoneal cavity-derived cells. Restoration of anti-chondrocyte activity of nonadherent SPL to the level comparable with that of untreated SPL was achieved with about 10% of adherent cells. On the other hand, reconstitution of nonadherent PC did not result in an increase of chondrocyte lysis. Potentiation of nonadherent SPL activity was seen only with syngeneic M phi, and the latter could not be replaced by conditioned media which were generated in the 18-hr culture of adherent SPL or PC.
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PMID:Natural anti-chondrocyte cytotoxic activity in the mouse: supportive role of macrophages. 210 63

Myelodysplastic syndromes (SMD) were studied in 58 patients (37 men, 21 women; mean age 61 years, range 18-81) who were grouped according to FAB criteria (Table 1). None of them showed a secondary SMD to medullary toxic agents or cytostatic treatments although 5 presented concomitant neoplastic disease. Morphologic alterations in peripheral blood smears and bone marrow were registered by 3 hematologists working independently. The intracellular and extracellular iron deposits were evaluated in every case with Perls; peroxidase activity was determined in 16 patients and intraleucocitary alkaline phosphatase reaction was carried out in 17 patients. Twenty five patients (43%) had refractory anemia (RA); 10 (17%) sideroblastic anemia; 13 (25%) refractory anemia with excess of blasts (AREB); 3 (5%) AREB in transformation (AREB-T) and 7 myelomonocytic leukemia (LMMC). Clinical manifestations at diagnosis are described in Table 2. In the observation period there were cases of anemia requiring transfusion, bacterial infections, muco-cutaneous hemorrhage and hemorrhagic episodes in the central nervous system. In the bone marrow smears the cellularity was normal or increased in 53 cases and diminished in only 3. The degree of dysplastic characteristics (erythroid, granulocytic and megakaryocytic) ranged from low to severe. It was low in most of AR, being the erythroid population the most affected in AS and the granulocytic one in AREB and AREB-T. Patients with LMMC showed similar characteristics to those with myeloproliferative syndromes and the differential diagnosis were sometimes difficult, accounting for their separate inclusion in Table 4. Out of 23 patients, 5 presented clonal pathology detected in cytogenetic studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Myelodysplastic syndrome: experience of the Study and Treatment of Bone Marrow Failure Group]. 213 Feb 4

Ga-67 urinary excretion was examined in 59 patients. The 72-hour urinary excretion rate ranged from 4.3 to 67.8% of the injected dose. Within the first 24 hours, 60.9% of the 72-hour urinary excretion was excreted. There was no significant difference in the Ga-67 urinary excretion rate between males and females, nor between the Ga-67 positive and negative cases. A significant negative correlation was found between the 72-hour Ga-67 urinary excretion rate and the unsaturated iron binding capacity. Notably, four patients with hyperferremia, which was considered secondary to leukemia and/or chemotherapy or liver cirrhosis, excreted more than 46.8% of Ga-67 within 72 hours. A significant negative correlation was also found between the 72-hour Ga-67 urinary excretion rate and age. Urinary excretion of Ga-67 may be related to the glomerular filtration rate, which decreases with age.
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PMID:Clinical study of urinary excretion of Ga-67. 234 Jun 60

Hemin inhibited 59Fe uptake from transferrin (Tf) by mouse erythro-leukemia cells (MELC) induced for differentiation by hexamethylene bisacetamide (HMBA), but the rate and the extent of 125I-Tf endocytosis was unaffected. Hemin inhibited 59Fe incorporation into heme by a greater proportion than the overall uptake of 59Fe from Tf. Desferrioxamine (DFO) reverted the inhibition of 59Fe transport into MELC caused by hemin. Exogenous 5-aminolevulinic acid (ALA) stimulated 59Fe utilization for heme synthesis in MELC but did not revert inhibition induced by hemin. No evidence for a direct effect of heme on the Tf cycle or iron release was found.
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PMID:The relationship between heme synthesis and iron uptake in erythroid cells. 238 33

We investigated the effects of the iron chelator desferrioxamine on the expression of transferrin receptors (TfR) by CCRF-CEM human T-cell leukaemia and B16 mouse melanoma cells growing in tissue culture. Desferrioxamine (DFOA) enhanced TfR expression when added in the dose range of 10(-5)-10(-4) to CCRF-CEM cells, but was toxic to these cells, the lower concentrations producing a slowing of cell growth with a build up in S-phase, while higher concentrations caused cell death with a block at the G1/S-phase interface. These toxic effects are compatible with its previously reported inhibition of the non-haem iron containing (M2) subunit of ribonucleotide reductase. In marked contrast, DFOA caused the growth of B16 melanoma cells to arrest in G1, without loss of cloning efficiency, and resulted in a fall in TfR expression to approximately 50% of control values. These results suggested that the effects of DFOA on TfR expression were linked to DNA synthesis rather than to a more generalised inhibition of iron-dependent cellular processes. It was subsequently found that inhibition of the M2 subunit of ribonucleotide reductase in CCRF-CEM cells with 5 X 10(-5) M hydroxyurea, which is not an iron chelator, also enhanced TfR expression, as did thymidine and cytosine arabinoside, which have different enzyme targets. By measuring cellular DNA and RNA content simultaneously it was shown that all of these agents caused unbalanced growth, i.e., inhibited DNA synthesis more than RNA synthesis. In contrast, 6-thioguanine was more inhibitory to RNA synthesis, and treatment with this drug caused a fall in TfR expression. Thus, although CCRF-CEM cells treated with DFOA show enhanced TfR expression, similar effects are also seen with other inhibitors of DNA synthesis, provided that RNA synthesis is allowed to continue. These results provide further evidence that the regulation of TfR expression by proliferating cells is specifically linked to DNA synthesis rather than to the iron requirements of other cellular processes.
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PMID:Modulation of transferrin receptor expression by inhibitors of nucleic acid synthesis. 241 49

Numerous investigators have demonstrated that derangements in serum transferrin and iron can contribute to susceptibility to infection, but the complexity and imprecision of assays have impeded both research and development of clinical testing in this area. This article describes an automated assay for measuring the microbial inhibitory activity of transferrin in serum and its use in patients with acute myelogenous leukemia (AML) and in normal controls. The assay measured the ability of heat-inactivated serum to inhibit the growth of an antibiotic-resistant strain of Pseudomonas aeruginosa. The serum dilutions were prepared in a special low iron chemically defined broth. An inhibition index, the reciprocal of the serum dilution producing 50% inhibition of bacterial growth when compared with the growth in broth alone, was determined. The results showed the serum from the patients with leukemia had a significantly lower inhibition index than that of controls (16 +/- 11 vs. 35 +/- 13, P less than 0.01). In addition, they had higher serum iron levels (162 +/- 65 vs. 75 +/- 27, P less than 0.01), lower serum transferrin levels (231 +/- 65 vs. 309 +/- 71, P less than 0.01), and higher percentage saturation of transferrin with iron (59 +/- 21 vs. 20 +/- 8, P less than 0.01) than did controls. Because the assay uses equipment available in many clinical laboratories, it could be developed for routine use as an index of susceptibility to infection in selected patients.
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PMID:An improved method for determining the microbial inhibitory activity of serum and its application to the study of patients with leukemia. 250 6

As an iron-chelating agent, deferoxamine (DFO) is widely used in treating iron poisoning and disorders of iron overload. This study demonstrates that DFO is a potent S-phase inhibitor of DNA synthesis in human lymphocytes in vitro, and this inhibitory effect of DFO is reversible by adding appropriate amounts of ferric ion. As a nontoxic and selective-S-phase inhibitor, it may play a role in immunosuppression in experimental and therapeutic situations. It may even become an auxiliary therapy for leukemia or other malignant tumors.
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PMID:The inhibitory effect of deferoxamine on DNA synthesis in human lymphocytes. 251 33

The expression of transferrin receptors (TrfRs) was investigated in acute T-cell leukemia (T-ALL) blasts at the molecular, biochemical, immunological, and functional level. TrfRs, although not detected on quiescent T-cells from normal adults, are constitutively expressed at high level on the blasts from all T-ALL patients and bind normally to transferrin. Their number is modulated by the intracellular iron level, but is independent of exogenous interleukin 2. They also exhibit immunological and biochemical abnormalities, in that: (a) they react preferentially with monoclonal antibodies (MAb) that recognize ligand-binding domains of TrfR (42/6 and 43/31), as compared to MAbs (B3/25, OKT9) that interact with the nonligand binding domains; (b) they have a reduced molecular weight, as compared to TrfR on normal thymocytes and activated T-lymphocytes: this phenomenon is apparently related to a defective glycosylation. It is noteworthy that expression of TrfR was not observed in a large series of other types of acute leukemias, i.e., pre-B, B, and myeloid leukemias, excluding erythroleukemias. The constitutive, high level expression of TrfRs on T-ALL blasts may play a key role in the stepwise progression of this malignancy and particularly provide a proliferative advantage to T-ALL blasts as compared to normal T-lymphocytes. Furthermore, indirect evidence suggests that the glycosylation defect of TrfR on T-ALL blasts contributes to their tumorigenic capacity.
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PMID:Constitutive expression and abnormal glycosylation of transferrin receptor in acute T-cell leukemia. 258 41

Iron (Fe) depletion with anti-transferrin (Tf) receptor monoclonal antibodies (MAbs), Fe chelators, or gallium (Ga) salts inhibits in vitro and in vivo growth of tumor cells. The present studies examined the cytotoxic effects of an IgA anti-human Tf receptor MAb, 42/6, combined with parabactin, a powerful Fe chelator, or Ga nitrate. Parabactin inhibited in vitro growth of human hematopoietic and solid tumor cells, and the rank order of their sensitivities to the Fe chelator was identical to their relative sensitivity to MAb 42/6 as demonstrated in previous studies. When the most parabactin and MAb 42/6-sensitive (HL60 leukemia) and -resistant (KB carcinoma) cells were incubated with various concentrations of parabactin, cell killing was time and dose dependent over the first 24 hours. Little additional cytotoxicity occurred, however, when cells were exposed to parabactin for 48 hours. HL60 cells were slightly more sensitive than KB cells to parabactin cytotoxicity. Addition of optimally effective concentrations of anti-Tf receptor MAb 42/6 to parabactin increased cytotoxicity to HL60 cells over a narrow parabactin dose range but had little effect on cytotoxicity to KB cells. Cell cycle analysis of cells treated with parabactin for 24 hours showed that doses causing variable cytotoxicity increased the percentage of cells in S phase, but higher parabactin concentrations consistently arrested cells in G1 phase or at the G1/S interface. MAb 42/6 also increased toxicity of parabactin to granulocyte/macrophage colony-stimulating factors and normal marrow granulocyte/macrophage progenitors. When HL60 or KB cells were treated with MAb 42/6 combined with Ga nitrate, MAb 42/6 increased cytotoxicity of Ga for HL60 cells but had little or no effect on Ga cytotoxicity to KB cells. In contrast, MAb 42/6 had minimal effects on cytotoxicity of the ribonucleotide reductase inhibitor, isoquinaldehyde thiosemicarbazone, to either HL60 or KB cells. Both hematopoietic and solid tumors were killed by Fe depletion, but the present studies suggested that hematopoietic cells are more sensitive than solid tumor cells to cytotoxic effects of Fe depletion. Combined Fe depletion therapy by the use of MAb 42/6 with an Fe chelator or Ga salt increased toxicity to MAb 42/6-sensitive cells, such as HL60, but was not more effective against MAb 42/6-resistant solid tumor cells. Combination Fe depletion therapy of hematopoietic cell tumors merits evaluation in experimental in vivo tumor systems.
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PMID:Combination iron depletion therapy. 266 76


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