1,25-DIHYDROXYVITAMIN D-3 AND ITS ANALOGS INHIBIT ACUTE MYELOGENOUS LEUKEMIA PROGENITOR PROLIFERATION BY SUPPRESSING INTERLEUKIN-1-BETA PRODUCTION

We hypothesized that 1,25-dihydroxyvitamin D-3 (1,25D(3)) and its anal ogues may inhibit acute myelogenous leukemia (ARIL) proliferation by i nterrupting IL-1 beta-mediated growth-stimulatory signals, The incubat ion of the IL-1 beta-responsive AML cell line OCIM2 with 10 nhl 1,25D( 3) reduced growth 80% in liquid culture, and a 100-1000-fold lower con centration of 20-epi analogues (MC1288 and MC1301) was sufficient to a chieve similar growth inhibition, The growth inhibition was associated with a rapid but transient downregulation of IL-1 beta and IL-1 beta- converting enzyme (ICE) mRNAs in 1,25D(3)- and 20-epi analogue-treated cells, and the 20-epi analogue was more effective than 1,25D(3) in re pressing ICE expression, An examination of long-term changes in the le vels of mature IL-1 beta and its precursor revealed that 24-h incubati on of OCIM2 with either 1,25D(3) or its 20-epi analogues abolished the production of mature IL-1 beta. The effect of 1,25D(3) and its analog ues on growth of fresh bone marrow cells from seven AML patients was t ested by a clonogenic assay, Growth inhibition of 60% was reached in o nly one of seven 1,25D(3)-treated samples, but all seven samples were inhibited 60-90% by the 20-epi analogue MC1301, Growth inhibition by 1 ,25D(3) and the analogue was reversible by addition of IL-1 beta. Thes e results suggest that 1,25D(3) and its 20-epi analogues interrupt IL- 1 beta autocrine growth regulation by inhibiting IL-1 beta production and processing but not the response to IL-1 beta.