Telomerase contributes to fludarabine resistance in primary human leukemic lymphocytes.
We report that Imetelstat, a telomerase inhibitor that binds to the RNA component of telomerase (hTR), can sensitize primary CLL lymphocytes to fludarabine in vitro. This effect was observed in lymphocytes from clinically resistant cases and with cytogenetic abnormalities associated with bad prognosis. Imetelstat mediated-sensitization to fludarabine was not associated with telomerase activity, but with the basal expression of Ku80. Since both Imetelstat and Ku80 bind hTR, we assessed 1) if Ku80 and Imetelstat alter each other's binding to hTR in vitro and 2) the effect of an oligonucleotide complementary to the Ku binding site in hTR (Ku oligo) on the survival of primary CLL lymphocytes exposed to fludarabine. We show that Imetelstat interferes with the binding of Ku70/80 (Ku) to hTR and that the Ku oligo can sensitize CLL lymphocytes to FLU. Our results suggest that Ku binding to hTR may contribute to fludarabine resistance in CLL lmphocytes. This is the first report highlighting the potentially broad effectiveness of Imetelstat in CLL, and the potential biological and clinical implications of a functional interaction between Ku and hTR in primary human cancer cells.
Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
May
M
Shawi
Tsz Wai
TW
Chu
Veronica
V
Martinez-Marignac
Y
Y
Yu
Sergei M
SM
Gryaznov
James B
JB
Johnston
Susan P
SP
Lees-Miller
Sarit E
SE
Assouline
Chantal
C
Autexier
Raquel
R
Aloyz
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain / Q000187:drug effects; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D000072200:Ku Autoantigen; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009841:Oligonucleotides; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D019098:Telomerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D019098:Telomerase; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; C519562:imetelstat; D014740:Vidarabine; C024352:fludarabine