cholecalciferol and Leukemia--Erythroblastic--Acute

We report on two cases of patients who developed diabetes insipidus (DI) before acute erythroleukaemia (EL). A brain MRI showed an empty sella turcica in one case and hypothalamo-hypophyseal peduncle damage in the second case. Reduced levels of TGF-beta1 and Vitamin D3, with associated EVI-1 over-expression and karyotypic abnormalities were documented. These two cases show specific chromosomal/molecular alterations in EL with DI. The hypothesis of pituitary involvement in erythroleukemogenesis is discussed.

Topics: Adult; Cholecalciferol; Chromosome Aberrations; Diabetes Insipidus; DNA-Binding Proteins; Empty Sella Syndrome; Female; Humans; Hypothalamic Diseases; Leukemia, Erythroblastic, Acute; Magnetic Resonance Imaging; Male; MDS1 and EVI1 Complex Locus Protein; Middle Aged; Pituitary Gland; Proto-Oncogenes; Transcription Factors; Transforming Growth Factor beta1

1alpha,25-Dihydroxyvitamin D3 (1alpha,25-(OH)2D3) and other vitamin D3 (VD3) analogs enhanced the inhibitory effect of Activin A on murine erythroleukemia (MEL) cell proliferation and differentiation in a dose-dependent manner. 1alpha,25-(OH)2D3 inhibited differentiation more potently than proliferation by one order of magnitude. The VD3 analog study demonstrated either effect of VD3 on MEL cells via vitamin D receptor (VDR), as evidenced from the close relationship with the reported affinities for VDR. The effects of 1alpha,25-(OH)2D3 were preceded by the suppression of ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine metabolism. Difluoromethylornithine (DFMO), an inhibitor of ODC, inhibited MEL cell proliferation, which was reversed by the simultaneous addition of putrescine, a product of ODC, but did not affect differentiation. 1alpha,25-(OH)2D3 inhibited cell differentiation during the phenotype-expression stage as reflected by the inhibition of beta-globin gene expression, while it inhibited proliferation in the commitment stage. Furthermore, it seems unlikely that the different effects of VD3 on proliferation and differentiation may be a result of upregulation of VDR or nongenomic action. In summary, it was suggested that 1alpha,25-(OH)2D3 inhibited Activin A-induced MEL cell proliferation and differentiation by distinct mechanisms and inhibited the proliferation by inhibiting ODC activity. We demonstrated the presence of 1alpha,25-(OH)2D3 action on leukemic cells at physiological concentration, which was distinct from the pharmacological effect of VD3 reported thus far.

Topics: Acetyltransferases; Activins; Animals; Calcitriol; Cell Differentiation; Cell Division; Cell Line; Cholecalciferol; Eflornithine; Gene Expression Regulation, Neoplastic; Globins; Growth Substances; Inhibins; Kinetics; Leukemia, Erythroblastic, Acute; Mice; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitors; Polyamines; Proto-Oncogene Proteins c-kit; Receptors, Calcitriol; Tumor Cells, Cultured

A number of vitamin D3 metabolites inhibit benzodiazepine- and dimethyl sulfoxide-induced differentiation of Friend erythroleukemia cells. The inhibition is dose dependent and occurs at nM concentrations. The order of potency of these compounds is 1,25-dihydroxycholecalciferol greater than 1,25,26-trihydroxycholecalciferol greater than 1,24R,25-trihydroxycholecalciferol greater than 1 alpha-hydroxycholecalciferol greater than 24R,25-dihydroxycholecalciferol greater than 25S,26-dihydroxycholecalciferol. The inhibition is maximal when the vitamin D3 analogs are added together with the inducer, and becomes progressively decreased with delayed addition. These results suggest that the vitamin D3 metabolites may play a regulatory role in erythropoiesis.

Topics: Animals; Calcitriol; Cell Differentiation; Cell Line; Cholecalciferol; Dimethyl Sulfoxide; Kinetics; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Mice; Structure-Activity Relationship