Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by 1,25-dihydroxyvitamin D3 and its fluorinated analogues.
This study shows for the first time that 1,25-dihydroxyvitamin D3[1,25-(OH)2D3] and two fluorinated analogues of 1,25-(OH)2D3 [24,24-F2-1,25-(OH)2D3 and 26, 26, 26, 27, 27, 27-F6-1,25-(OH)2D3] induce macrophage differentiation of human normal and leukemic myeloid stem cells. The addition of either 1,25-(OH)2D3 or one of the two fluorinated analogues of 1,25-(OH)2D3 at concentrations as low as 10(-9) M to culture plates containing normal human marrow cells stimulated myeloid stem cells to preferentially differentiate to colonies of monocytes and macrophages. Over 80% of the normal human myeloid colonies were composed of only monocytes and macrophages in culture plates containing 10(-7) M 1,25-(OH)2D3 or one of the fluorinated analogues. In contrast, control plates not containing 1,25-(OH)2D3 had less than 35% macrophage colonies. Likewise, 1,25-(OH)2D3 and the two vitamin D analogues induced macrophage differentiation of leukemic colony-forming cells taken from patients. In plates containing 10(-7) M 1,25-(OH)2D3 or one of the analogues at 10(-8) M, 80% of chronic myelogenous leukemia and approximately 50% of acute nonlymphocytic leukemia colony-forming cells differentiated to macrophage-like cells. In contrast, control plates had about 30 and 20% macrophage colonies in cultures from chronic myelogenous leukemia and acute nonlymphocytic leukemia patients, respectively. Our findings suggest that 1,25-(OH)2D3 may play a role in hematopoiesis and that the compound or a related analogue may possibly have a therapeutic role in some leukemias.
D001853:Bone Marrow / Q000473:pathology; D001854:Bone Marrow Cells; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D007951:Leukemia, Myeloid / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D012016:Reference Values; D013329:Structure-Activity Relationship; D005466:Fluorocarbons
D002117:Calcitriol; C023370:24,24-difluoro-1,25-dihydroxyvitamin D3; C040488:26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3; D005466:Fluorocarbons