vitamin-b-12 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Vitamin B 12

Serum cobalamin and homocysteine levels were studied in patients with chronic myelogenous leukemia (CML) and in stem cell donors treated with granulocyte-colony stimulating factor (G-CSF). Cytoreductive treatment in patients with CML resulted in a decrease of cobalamin and homocysteine levels. In stem cell donors cobalamin and homocysteine levels increased after G-CSF administration. The increase of homocysteine level was accompanied by a decrease in the serum levels of the cobalamin-binding protein transcobalamin. We hypothesize that the increased homocysteine levels in patients with CML and donors treated with G-CSF may be the result of a functional methylcobalamin deficiency due to decreased transcobalamin levels.

Topics: Granulocyte Colony-Stimulating Factor; Humans; Hyperhomocysteinemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Diagnosis, Differential; Female; Folic Acid; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Radioimmunoassay; Vitamin B 12

The plasma protein transcobalamin II (TCII) binds and delivers cobalamin (Cbl; vitamin B12) to all cells, which internalize the TCII/Cbl complex by receptor-mediated endocytosis. Congenital deficiency of TCII results in intracellular Cbl deficiency, one effect of which is to disrupt DNA synthesis, leading to megaloblastic anemia. We report here an in vitro culture system in which cell growth is dependent on delivery of Cbl to cells by TCII. Recombinant human holo-TCII was shown to support in dose-dependent manner the growth of the human erythroleukemic cell line K562 and the murine lymphoma cell line BW5147. Free Cbl also supported cell growth; however, at 100- to 1,000-fold higher concentrations than those effective in the presence of apo-TCII. To determine if cellular depletion of Cbl could be achieved by interfering with interactions between TCII/Cbl and its cell-surface receptor, several monoclonal antibodies raised against human TCII were studied. Three antibodies, found to compete for the same binding site on TCII, proved to be effective inhibitors of TCII/Cbl-dependent cell growth. Our results suggest that monoclonal anti-TCII antibodies that block the function of this protein may prove useful in antitumor therapies.

Topics: Antibodies, Monoclonal; Apoptosis; Cell Division; Folic Acid; Growth Inhibitors; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma; Neoplastic Stem Cells; Transcobalamins; Tumor Cells, Cultured; Vitamin B 12

Topics: Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocyte Count; Leukocytes; Male; Prognosis; Transcobalamins; Vitamin B 12

The cobalamin metabolism in chronic myelogenous leukemia (CML) was evaluated in 18 newly diagnosed and untreated patients by formiminoglutamic acid (FiGlu) and methyl malonic acid excretion (MMA) tests. A deoxyuridine (dU) suppression test of bone marrow cells was compared in patients with acute myelogenous leukemia (N = 5), myelodysplastic disease (N = 3), untreated pernicious anemia (N = 16), folate deficiency (N = 7), and a hospital reference group without signs of cobalamin or folate deficiency (N = 22). All had normal MMA excretion but 3 of 15 patients had increased FiGlu excretion. In vitro thymidine uptake in bone marrow cells of CML patients were lower (mean 40 fmol/106 cells) than pernicious anemia patients (115 fmol/106 cells). Methotrexate (MTX) increased the uptake in all cases. Addition of formyl-THF, methyltetrahydrofolate (methyl-THF), and pteroylglutamic acid (PGA) tended to normalize the effect of MTX. In pernicious anemia methyl-THF only decreased the uptake in combination with CN-Cbl. dU suppression values were significantly higher (6.3%) in CML than in the reference group (4.4%), but significantly lower than in pernicious anemia (41.6%) and folate deficiency (28.5%). The dU suppression values in bone marrow cells of CML patients correlated significantly with the transferrin saturation. In buffy coat cells dU suppression values were even higher (9.3%) than in bone marrow cells of the same CML patients. Addition of folate forms and CN-Cbl did not change the dU suppression values in CML, as it did in pernicious anemia. MTX increased dU suppression values significantly in all patients, but more in CML (64.5%) than in pernicious anemia (48.6%) and controls (49.8%). The MTX effect was to some extent neutralized by folate analogues with formyl-THF as the most effective followed by methyl-THF and lastly PGA. Methyl-THF also neutralized MTX in pernicious anemia, but its effect was certainly enhanced by addition of CN-Cbl. Thymidine uptake and dU suppression patterns were not significantly changed in CML after treatment with busulfan for 1 week or in accelerated phase. We concluded that signs of cobalamin or folate deficiency (apart from one patient) cannot be demonstrated in untreated CML. However, dU suppression was significantly increased and more so in circulating myeloid cells than in bone marrow. This indicates a deranged metabolism of deoxynucleotides which is independent of cobalamin and folates, and a difference between bone marrow cell

Topics: Adolescent; Adult; Aged; Bone Marrow; Bone Marrow Cells; Deoxyuridine; Female; Formiminoglutamic Acid; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Malonates; Methotrexate; Middle Aged; Tetrahydrofolates; Thymidine; Tritium; Vitamin B 12

Plasma and buffy coat specimens of CML patients with untreated disease, in chronic and accelerated phase, and in overt blastic crises were analysed for the cobalamin patterns using non-polar extraction, thin-layer chromatography and bioautography. Splenic tissue specimens from four splenectomized patients in accelerated phase were analysed similarly. Cellular extracts were separated into two compartments by adsorption to haptocorrin antibodies. Plasma concentrations of all cobalamin forms were increased in CML. The proportion of methylcobalamin was significantly lower than in a reference population, and a low plasma proportion of methylcobalamin was associated with a poor prognosis. Buffy coat cells and splenic tissue had a higher proportion of 5'-deoxyadenosylcobalamin and a lower proportion of methylcobalamin than plasma; still, there was relatively more methylcobalamin than in normal tissue. The haptocorrin-bound compartment differed from the non-haptocorrin compartment in untreated or chronic phase patients by binding less methylcobalamin. An estimate of cobalamin analogues in plasma was achieved by comparing two different isotope dilution assays employing a cobalamin-specific binder, intrinsic factor, and a nonspecific binder, hog non-intrinsic factor. Values for total cobalamin and analogues were increased to the same degree in CML plasma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chromatography, Thin Layer; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukocytes; Male; Middle Aged; Spleen; Splenectomy; Vitamin B 12

Individual plasma specimens from six patients with chronic myelogenous leukemia (CML) in chronic phase were incubated with [57Co]cyanocobalamin and injected into patients to study the turnover of cobalamin bound to haptocorrin and transcobalamin. The [57Co] radioactivity bound to haptocorrin and transcobalamin was determined after separating the proteins by adsorption to insolubilized antibodies to haptocorrin. The distribution of the radioactivity on the different forms of cobalamin and on haptocorrin isoproteins were determined. The fractional catabolic rate of hapatocorrin (0.102 to 0.158 d-1) and transcobalamin (3 to 29 d-1) was of the same magnitude as previously reported for a reference population. During the first 24 hours of the turnover, no change of the cyanocobalamin form was registered, indicating that conversion of cyanocobalamin to the coenzyme forms of cobalamin does not take place in the circulation. The haptocorrin isoprotein pattern changes in alkaline direction during the first 5 hours indicated that the glycoprotein was desialinated during circulation. From the calculated turnover parameter, the possible competition between transcobalamin and haptocorrin for the transport of cobalamins in CML is estimated to be of minor clinical significance. In conclusion, the increased plasma concentration of haptocorrin in CML is due to an increased liberation of haptocorrin and is not due to a decreased turnover of the protein.

Topics: Adult; Aged; Biological Transport; Cobalt Radioisotopes; Female; Half-Life; Humans; Kinetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Transcobalamins; Vitamin B 12

Although vitamin B12 is an essential coenzyme for DNA synthesis, humans, like other mammals, are incapable of synthesizing it. The role of intrinsic factor (IF) in B12 absorption is widely known, but, in fact there exists a much more intricate and complex mechanism for the effective assimilation of this important trace element in humans. B12 binding proteins play important roles in all stages of vitamin B12 metabolism. They are involved not only in its absorption, but also in its transport in serum, uptake to cells, storage in organs, enterohepatic circulation, and elimination of its analogues. Besides IF, well-known as a vitamin B12 binding protein found in gastric juice, there are other kinds of binding proteins found in human serum which are composed to transcobalamin (TC) I, II and III. Elevation of the vitamin B12 level in chronic myelogenous leukemia was first reported in the 1950s. Since then, B12 elevation has been found to occur in other kinds of chronic myeloproliferative disorders (CMPDs) as well and to be caused by an increase of serum TC. In CMPDs, either TCI or TCIII increases, but, the degree of elevation and the type of TC involved differs for each disorder. This article describes the changes in TC of CMPD patients. With the induction of the developed radioimmunoassay for R-type B12 binding protein, many cases have been examined. In addition, detailed qualitative analysis using DEAE cellulose column chromatography has been included for conditions not previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blast Crisis; Chronic Disease; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloproliferative Disorders; Transcobalamins; Vitamin B 12

Topics: Anemia; Anemia, Pernicious; Blood; Hepatitis; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Vitamin B 12

Topics: Biological Transport; Blood; Blood Proteins; Cobalt Isotopes; Corrinoids; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Metabolism; Vitamin B 12

Topics: Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Vitamin B 12

Topics: Corrinoids; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Vitamin B 12

Topics: Anemia; Anemia, Pernicious; Hematinics; Humans; Kinetics; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Vitamin B 12

Topics: Busulfan; Hematinics; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Mercaptopurine; Vitamin B 12

Topics: Hematinics; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Liver Diseases; Serum; Vitamin B 12

Topics: Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Orosomucoid; Plasma; Vitamin B 12

Topics: Blood Proteins; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Transcobalamins; Vitamin B 12

Topics: Blood Proteins; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Transcobalamins; Vitamin B 12

Topics: Biological Transport; Cobalt; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Plasma; Tissue Distribution; Vitamin B 12

Topics: Corrinoids; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myelitis; Vitamin B 12

Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelitis; Vitamin B 12

Topics: Corrinoids; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myelitis; Vitamin B 12