losartan-potassium and Leukemia--Promyelocytic--Acute

Vitamin A is an essential micronutrient throughout life. Its physiologically active metabolite retinoic acid (RA), acting through nuclear retinoic acid receptors (RARs), is a potent regulator of patterning during embryonic development, as well as being necessary for adult tissue homeostasis. Vitamin A deficiency during pregnancy increases risk of maternal night blindness and anemia and may be a cause of congenital malformations. Childhood Vitamin A deficiency can cause xerophthalmia, lower resistance to infection and increased risk of mortality. RA signaling appears to be essential for expression of genes involved in developmental hematopoiesis, regulating the endothelial/blood cells balance in the yolk sac, promoting the hemogenic program in the aorta-gonad-mesonephros area and stimulating eryrthropoiesis in fetal liver by activating the expression of erythropoietin. In adults, RA signaling regulates differentiation of granulocytes and enhances erythropoiesis. Vitamin A may facilitate iron absorption and metabolism to prevent anemia and plays a key role in mucosal immune responses, modulating the function of regulatory T cells. Furthermore, defective RA/RARα signaling is involved in the pathogenesis of acute promyelocytic leukemia due to a failure in differentiation of promyelocytes. This review focuses on the different roles played by vitamin A/RA signaling in physiological and pathological mouse hematopoiesis duddurring both, embryonic and adult life, and the consequences of vitamin A deficiency for the blood system.

Topics: Anemia, Iron-Deficiency; Animals; Cell Differentiation; Disease Models, Animal; Embryonic Development; Epigenesis, Genetic; Erythropoiesis; Erythropoietin; Female; Granulocytes; Hematopoiesis; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Receptors, Retinoic Acid; Signal Transduction; Tretinoin; Vitamin A; Vitamin A Deficiency

Topics: Adult; Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Erythropoietin; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Oxides; Reticulocyte Count

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Erythropoietin; Female; Hemoglobins; Humans; Jehovah's Witnesses; Leukemia, Promyelocytic, Acute; Male; Mercaptopurine; Methotrexate; Middle Aged; Remission Induction; Treatment Outcome; Tretinoin

Iron overload may induce liver toxicity after hematopoietic stem cell transplantation (HSCT), but it is not known if iron depletion prior to HSCT can reduce the risk of severe toxicity in this setting. We used subcutaneous recombinant erythropoietin (EPO) (25 UI/kg) three times a week and phlebotomy once a week, to prevent liver toxicity in a patient with advanced acute leukemia and liver disease due to severe iron overload, previous drug toxicity and hepatitis C viral infection. Over the 9 months prior to allogeneic HSCT, 34 phlebotomies were carried out. Serum ferritin dropped from 2964 to 239 microg/l and the ALT dropped to near normal values. At allogeneic HSCT no liver toxicity was observed, suggesting that iron depletion in the pretransplant period may contribute to reducing transplant-related toxicity in selected cases.

Topics: Adult; Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Humans; Iron Overload; Leukemia, Promyelocytic, Acute; Liver; Phlebotomy; Recombinant Proteins; Transplantation, Homologous

Endogenous serum thrombopoietin (TPO) and various cytokines including erythropoietin (EPO), interleukin (IL)-3, IL-6, IL-11, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF) and stem cell factor (SCF) levels were measured in five patients with acute promyelocytic leukaemia (APL) during all-trans retinoic acid (RA) treatment. During differentiation-inducing therapy, platelet counts slowly increased and reached a peak between days 29 and 46 (median day 35). Serum TPO levels increased parallel to the increasing platelet counts and reached a maximum level during the first 10-20 d of all-trans RA treatment. The circulating TPO levels then decreased in inverse correlation to the platelet counts. These unique changes in serum TPO levels revealed that TPO levels were not regulated by platelet or megakaryocyte mass in patients with APL during differentiation-inducing therapy, and it would appear that TPO levels are directly regulated by all-trans RA during the first 10-20 d of treatment. In addition, the change in circulating EPO levels and reticulocyte counts were similar to that of the TPO levels and platelet counts during all-trans RA treatment, suggesting a close relationship between TPO and EPO signalling.

Topics: Adult; Erythropoietin; Female; Humans; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Platelet Count; Thrombopoietin; Treatment Outcome; Tretinoin

We recently established an acute promyelocytic leukemia (APL) cell line (HT93) that has the capacity to differentiate into neutrophils and eosinophils in response to all-trans retinoic acid (ATRA) and human hematopoietic cytokines. The cells had a myeloblastic morphology, were positive for surface CD33, CD34, and CD56, and showed the following karyotypes: 46, XY, t(1;12)(q25;p13), 2q+, t(4;6)(q12;q13), and t(15;17)(q22;q11). When the cells were cultured with ATRA, they showed nuclear segmentation and developed secondary granules consisting in part of neutrophils and eosinophils. In the presence of ATRA and granulocyte colony-stimulating factor (G-CSF), the cells showed polymorphonuclear neutrophil differentiation accompanied by expression of surface CD11b, CD15, CD10, positive activity for neutrophil alkaline phosphatase (NAP), and NAP mRNA expression. In cultures with ATRA and granulocyte-macrophage colony-stimulating factor (GM-CSF), IL (interleukin)-3, or IL-5, HT93 showed remarkable eosinophil maturation at day 8 as determined by luxol fast blue staining, in addition to expression of eosinophil peroxidase and major basic protein. These results indicate that HT93 is an APL cell line with the ability to differentiate into neutrophils and eosinophils, and that these lineages are dependent on the CSF added. HT 93 should prove to be a useful model in analyzing the effects of hematopoietic cytokines on proliferation, differentiation, and maturation of hematopoietic progenitors.

Topics: Alkaline Phosphatase; Antigens, CD; Biomarkers; Cell Differentiation; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Eosinophils; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Interleukin-5; Karyotyping; Leukemia, Promyelocytic, Acute; Neutrophils; Peroxidase; Polymerase Chain Reaction; Recombinant Proteins; Translocation, Genetic; Tretinoin; Tumor Cells, Cultured

A 10-year-old boy with acute promyelocytic leukemia (APL) was treated with all-trans-retinoic acid (ATRA) at a dose of 60 mg/m2/day. Recombinant erythropoietin was also used. The patient parents and other relatives, all Jehova's Witnesses, refused any type of hemotherapy. After 43 days of ATRA treatment complete remission was obtained without the use of hemotherapy. This case exemplifies the advantages provided by ATRA treatment in APL.

Topics: Child; Christianity; Erythropoietin; Humans; Leukemia, Promyelocytic, Acute; Male; Recombinant Proteins; Tretinoin

Topics: Adult; Christianity; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Recombinant Proteins; Tretinoin

Topics: ABO Blood-Group System; Adolescent; Anemia; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Female; Humans; Immunologic Factors; Leukemia, Promyelocytic, Acute; Recombinant Proteins

Phenylalanine methylester (PME), a lysosomotropic compound can be used to deplete monocytes and myeloid cells from peripheral blood and bone marrow (BM). The potential of PME for purging leukemic cells from BM was investigated using U937 and HL-60 cell lines as models. Optimal purging conditions for U937 cells were determined using an MTT assay (3-4, 5-dimethylthiazol-2, 5-diphenyl tetrazolium biomide; Sigma). Elimination of U937 cells was time-, temperature-, and dose-dependent. PME activity was optimal at 37 degrees C for 45 minutes. Depletion of U937 was > 2.8 logs for 50 mmol/L PME. Compared with another purging agent, 100 micrograms/mL 4-hydroperoxycyclophosphamide had activity comparable to 40 mmol/L PME. HL-60 cells were even more sensitive to PME than U937 cells. To support observations made with the MTT assay, clonogenic assays were performed. PME, 50 mmol/L at 37 degrees C resulted in total depletion (> 5 logs) of U937 colonies. Progressive depletion of normal progenitor cells occurred when BM was incubated with PME at concentrations from 5 to 100 mmol/L. At 37 degrees C, 50 mmol/L PME reduced colony-forming units-granulocyte-macrophage and burst-forming units-erythroid (BFU-E) recovery by 98%. Recombinant human mast cell factor augmented BFU-E after PME treatment but had no effect on HL-60 or U937. These studies suggest that PME deserves further study as an agent for ex vivo marrow purging.

Topics: Bone Marrow; Bone Marrow Purging; Colony-Forming Units Assay; Cyclophosphamide; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Kinetics; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Phenylalanine; Recombinant Proteins; Stem Cell Factor; Time Factors; Tumor Cells, Cultured

A proportion of fetal liver hemopoietic blast cells express Fc gamma RII, and addition of the anti-Fc gamma RII monoclonal antibody CIKM5 induces a rise in calcium in these cells in suspension. Although these cells are thus capable of mobilizing intracellular calcium in response to surface receptor mediated events, neither granulocyte-macrophage colony-stimulating factor (GM-CSF) nor erythropoietin produced detectable changes in intracellular calcium ion concentration in these cells.

Topics: Antibodies, Monoclonal; Antigens, Differentiation; Calcium; Cell Line; Erythropoietin; Fetus; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cells; Humans; Immunoenzyme Techniques; Immunophenotyping; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid; Leukemia, Promyelocytic, Acute; Receptors, Fc; Receptors, IgG; Tumor Cells, Cultured