Telomerase inhibition by retinoids precedes cytodifferentiation of leukemia cells and may contribute to terminal differentiation.
Human promyelocytic leukemia HL60 cells display high telomerase activity, a phenotype related to their immortal status. All-trans retinoic acid (ATRA) is a clinically effective cytodifferentiating agent. To understand the mechanism underlying ATRA-induced cytodifferentiation, we did a kinetic analysis of the role of ATRA in inhibiting telomerase in HL60 cells. Our studies indicate that telomerase inhibition by ATRA occurred relatively early after treatment of HL60 cells due to a rapid decrease in hTERT gene expression. More importantly, however, we found through monitoring the expression of CD11b, a marker for granulocytic differentiation of HL60 cells, that down-regulation of telomerase preceded the differentiation of HL60 cells. These observations suggest that the hTERT gene may be a primary target of ATRA regulation of cellular differentiation and the antileukemia activity of ATRA may be mediated by its ability to induce the differentiation of the promyelocytic leukemia cells through down-regulation of the hTERT gene.
Department of Biology, University of Alabama-Birmingham, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294-1170, USA.
Liang
L
Liu
Joel B
JB
Berletch
Jessica G
JG
Green
Mitchell S
MS
Pate
Lucy G
LG
Andrews
Trygve O
TO
Tollefsbol
D039481:CD11b Antigen / Q000096:biosynthesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000378:metabolism*; D008954:Models, Biological; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure; D013997:Time Factors
D039481:CD11b Antigen; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D012176:Retinoids; D012313:RNA; D019098:Telomerase