ANTICOAGULANT EFFECTS OF 1-ALPHA,25-DIHYDROXYVITAMIN D-3 ON HUMAN MYELOGENOUS LEUKEMIA-CELLS AND MONOCYTES

The hormonally active form of vitamin D is 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3], which is a principal regulator of calcium homeo stasis. It also affects hormone secretion, cell differentiation, and p roliferation by a mode of action that involves stereospecific interact ion with an intracellular vitamin D receptor (VDR). We recently found that retinoids, which are vitamin A derivatives, exert anticoagulant e ffects by upregulating thrombomodulin (TM) and downregulating tissue f actor (TF) expression in acute promyelocytic leukemia cells and monobl astic leukemia cells. Both the VDR and retinoid receptors belong to th e same family of receptors. A heterodimer consisting of the retinoid X receptor and the VDR binds to vitamin D responsive elements on genes regulated by vitamin D. To determine whether 1,25(OH)(2)D-3 would exhi bit anticoagulant effects similar to retinoids, we measured the antige n level, activity, and mRNA level of TM and TF in human leukemic cells , vascular endothelial cells, and monocytes treated with 1,25(OH)(2)D- 3. We found that 1,25(OH)(2)D-3 upregulates antigen expression, activi ty, and mRNA levels of TM and downregulates antigen expression, activi ty, and mRNA levels of TF in human monocytic leukemia cells, some acut e myelogenous leukemia cells, and monocytes, but not in umbilical vein endothelial cells. Transient transfection studies with reporter plasm ids in monocytic leukemia cells and mobility gel-shift assay showed in teraction with 1,25(OH)(2)D-3 and functional retinoic acid responsive elements present in the 5'-flanking region of the TM gene. However, au xiliary factors or other elements in the TM gene may contribute to VDR specificity and transactivation of the gene in specific target cells. These findings indicate that 1,25(OH)(2)D-3 resembles the retinoids i n its control of the transcription of the TM and TF genes in human mon ocytic cells. Analogs of 1,25(OH)(2)D-3 with anticoagulant activity ma y serve as adjunctive antithrombotic agents in monocytic leukemia and atherosclerotic disease. (C) 1998 by The American Society of Hematolog y.