DIFFERENTIAL REGULATION OF VITAMIN-D RECEPTORS IN CLONAL POPULATIONS OF A CHRONIC MYELOGENOUS LEUKEMIA-CELL LINE

RWLeu4 is a chronic myelogenous leukemia cell line that is sensitive t o the antiproliferative and differentiation-inducing actions of 1 alph a, 25(OH)(2)-vitamin D-3 (VD3). The JMRD(3) cell line is a VD3-resista nt variant of RWLeu4 that was selected by continuous passage of RWLeu4 in the presence of VD3. The isolation of a spontaneous VD3-resistant variant suggests that phenotypically different cells exist within the RWLeu4 cell population. Therefore, single-cell clones of RWLeu4 cells were isolated and characterized. Four clonal cell populations that fal l into three groups differing in response to the antiproliferative and differentiation-inducing actions of VD3 were examined. Surprisingly, the extent of response of the clones to VD3 does not show a correlatio n with the basal level of the vitamin D receptor (VDR). RWLeu4-3 and R WLeu4-4 are the clones most sensitive to the antiproliferative actions of VD3 (ED(50) approximate to 1 nM); however, RWLeu4-3 expresses basa l levels of VDRs similar to those found in the parental cells and the RWLeu4-2 clone, while in RWLeu4-4, VD3 binding and VDR protein are bel ow the limits of detection. Furthermore, RWLeu4-10 expresses the highe st basal level of VDR protein but is relatively resistant to the antip roliferative actions of VD3 (ED(50) greater than or equal to 30 nM). L ike JMRD(3), RWLeu4-10 is still capable of differentiating in response to VD3, as judged by the induction of biochemical processes and cell- surface antigen expression, Although VD3 treatment increases VDR prote in levels and DNA-binding activity in all clones, altered DNA-protein complexes are detected in RWLeu4-4, Our results suggest that sensitivi ty to the antiproliferative and differentiation-inducing actions of VD 3 is not dependent solely upon the level of VDR expressed, but may als o require posttranslational modification of the VDR or complex interac tions with other nuclear transcription factors. (C) 1996 Academic Pres s, Inc.