losartan-potassium and Monosomy

Erythroid apoptosis in low-risk myelodysplastic syndrome (MDS) maybe mediated via mitochondrial release of cytochrome c and subsequent caspase activation. In the present study, we compared the in vitro and in vivo effects of proerythroid treatment with erythropoietin + granulocyte colony-stimulating factor (G-CSF) on myelodysplastic erythropoiesis regarding apoptosis and preferential growth of clones with cytogenetic abnormalities.. We enrolled 15 refractory anemia (RA) and 11 refractory anemia with ringed sideroblasts (RARS), including 5q- aberration, monosomy 7, and trisomy 8, before initiation of treatment and followed nine patients after successful treatment. The effects of G-CSF and erythropoietin were assessed. The expression of G-CSF receptor (G-CSFR) was explored during erythroid maturation. The relative growth of erythroid progenitors with cytogenetic aberrations in presence of erythropoietin was investigated.. Significant redistribution of cytochrome c was seen before treatment at all stages of erythroid differentiation. This release was blocked by G-CSF during the whole culture period and by erythropoietin during the latter phase. Both freshly isolated glycophorin A+ bone marrow cells and intermediate erythroblasts during cultivation retained their expression of G-CSFR. Cytochrome c release and caspase activation were significantly less pronounced in progenitors obtained from successfully treated nonanemic patients and showed no further response to G-CSF in vitro. Moreover, erythropoietin significantly promoted growth of cytogenetically normal cells from 5q- patients, whereas no such effect was observed on erythroblasts from monosomy 7 or trisomy 8 patients.. We conclude that growth factors such as erythropoietin and G-CSF can act both via inhibition of apoptosis of myelodysplastic erythroid precursors and via selection of cytogenetically normal progenitors.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Sideroblastic; Apoptosis; Bone Marrow Cells; Caspases; Cytochromes c; Enzyme Activation; Erythroid Precursor Cells; Erythropoietin; Glycophorins; Granulocyte Colony-Stimulating Factor; Humans; In Vitro Techniques; Middle Aged; Monosomy; Receptors, Granulocyte Colony-Stimulating Factor; Recombinant Proteins; Trisomy

A 9-year-old girl who had hepatitis-associated aplastic anemia was treated intermittently with methylprednisolone pulse therapy and growth factors (granulocyte-colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEpo) and cyclosporin A (CyA) for over two years. At this time, there was hematological improvement, but chromosome analysis revealed monosomy 7. After six months, there was progression to myelodysplastic syndrome (MDS) (stage in refractory anemia of excess blasts (RAEB)) with monosomy 7, monosomy 6, marker chromosome and with hematological deterioration. She received bone marrow (1.57 x 10(5) cells kg(-1) (patient body weight)) plus cord blood cell (0.3 x 10(7) cells kg(-1) (patient body weight)) transplantation from her brother, 2 years and 7 months after the diagnosis of hepatitis-associated aplastic anemia. Engraftment was achieved after two weeks, and acute graft-versus-host disease occurred in a mild form after four weeks. Hematological remission has been continuous for 20 months after bone marrow transplantation. Transformation of hepatitis-associated aplastic anemia to MDS with the monosomy 7, monosomy 6 and marker chromosome in this patient was considered to have been related to the administration of high doses of immunosuppressive drugs plus growth factors.

Topics: Anemia, Aplastic; Bone Marrow Transplantation; Child; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 7; Cord Blood Stem Cell Transplantation; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Growth Substances; Hepatitis; Humans; Immunosuppressive Agents; Monosomy; Myelodysplastic Syndromes; Recombinant Proteins; Transplantation, Homologous; Treatment Outcome

A cytogenetically normal man with severe aplastic anemia was treated with granulocyte colonystimulating factor (G-CSF), erythropoietin (EPO), cyclosporin A, anti-thymocyte globulin, and interleukin-6 (IL-6), which resulted in a gradual improvement in his neutrophil count and hemoglobin level. After 2 years of the therapy, monosomy 7 was detected during cytogenetic analysis of his bone marrow, which evolved during a period of 5 months into acute myeloblastic leukemia. An in vitro proliferation assay of cytokine responses showed that leukemic blasts were sensitive only to G-CSF, and not to EPO or IL-6. Although allogeneic bone marrow transplantation from an HLA-matched unrelated donor was carried out in the non-remission stage, the patient died of systemic fungal infection on day 25, without any evidence of hematological engraftment. As long-term use of cytokines and immunomo-suppressants in patients with severe aplastic anemia may induce or hasten the onset of a malignant transformation, careful attention must be paid to clonal evolution. Due to the poor prognosis of secondary myelodysplasia and leukemia, allogeneic bone marrow transplantation for such patients must be carried out early in the course of the disease.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Chromosomes, Human, Pair 7; Cyclosporine; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-6; Leukemia, Myeloid, Acute; Male; Monosomy

A 19-year-old man was diagnosed as having severe aplastic anemia and received high-dose methylprednisolone treatment without hematological response. A second course of high-dose mPSL treatment together with granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) was then started and resulted in trilineage blood cell response. Ten months after the combination therapy thrombocytopenia developed and cytogenetic analysis showed 45,XX,-7, indicating an evolution to myelodysplastic syndrome (MDS) associated with monosomy 7.G-CSF and EPO treatment together with immunosuppression may be an effective therapy in SAA patients, but such a therapy may increase the risk of evolution to MDS.

Topics: Adult; Anemia, Aplastic; Chromosomes, Human, Pair 7; Drug Therapy, Combination; Erythropoietin; Glucocorticoids; Granulocyte Colony-Stimulating Factor; Humans; Male; Methylprednisolone; Monosomy; Myelodysplastic Syndromes

A chronic myeloproliferative disorder associated with monosomy 7 is described in a 3 1/2-year-old boy. His presenting features closely resembled those of juvenile chronic myeloid leukaemia (JCML). Cytogenetic study of bone marrow cells showed that all of the metaphases examined had chromosome 7 deletions. He developed an erythroblastic phase, characterized by anaemia, marked erythroid hyperplasia of bone marrow and the appearance of nucleated red blood cells in the peripheral blood. During the erythroblastic phase, blood transfusion resulted in a suppression of erythropoiesis as evidenced in both the peripheral blood and bone marrow. The in vitro culture studies showed that the erythroid precursor was dependent upon erythropoietin (Ep) for differentiation and proliferation during the erythroblastic phase. However, the Ep dose-response curve showed that a peak of erythroid colony formation occurred at a lower concentration than in the healthy controls. These findings suggest that although the erythroid precursor remains under the control of Ep, it has an increased sensitivity to Ep during the erythroblastic phase of monosomy 7.

Topics: Blast Crisis; Blood Transfusion; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7; Erythropoiesis; Erythropoietin; Humans; Karyotyping; Male; Monosomy; Myeloproliferative Disorders