hTERT, the catalytic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia.
Telomere shortening is associated with disease progression in chronic myeloid leukaemia (CML). To investigate the biology and regulation of telomerase in CML, we evaluated expression of the telomerase components, its regulators and several telomeric-associated proteins. Quantitative real-time-polymerase chain reaction (PCR) was used to compare gene expression in the CD34+/leukaemic blast cells of 22 CML patient samples to the CD34+ cell population of healthy individuals. hTERT, the catalytic component of telomerase, was downregulated in eight of 12 chronic phase (CP) patients (P = 0.0387). Furthermore, hTERT was significantly downregulated in two of three patients in accelerated phase (AP) and seven of seven patients in blast crisis (BC), P = 0.0017. Expression of hTR and telomeric-associated proteins TEP1, TRF1, TRF2, tankyrase and PinX1 was high in the majority of CP and AP patients. With the exceptions of TEP1 and hTR, expression of these factors was highest in CP and decreased during disease progression. Expression of c-Myc, a positive regulator of hTERT transcription, correlated with hTERT expression and decreased with disease progression, falling below control levels in BC. hTERT levels were increased in CP patients following successful treatment with imatinib, relative to untreated CP patients. We suggest that reduced hTERT expression directly causes the shortened telomeres observed in CML.
Campbell
L J
LJ
Leukaemia Research Fund Molecular Haematology Unit, Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Fidler
C
C
Eagleton
H
H
Peniket
A
A
Kusec
R
R
Gal
S
S
Littlewood
T J
TJ
Wainscoat
J S
JS
Boultwood
J
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis; D001549:Benzamides; D002352:Carrier Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D012313:RNA / Q000096:biosynthesis; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D038501:Tankyrases / Q000096:biosynthesis; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000096:biosynthesis; D035341:Telomeric Repeat Binding Protein 2 / Q000096:biosynthesis; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
D018952:Antigens, CD34; D001549:Benzamides; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000068877:Imatinib Mesylate; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D012313:RNA; D016601:RNA-Binding Proteins; D038501:Tankyrases; D019098:Telomerase; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; D025521:Tumor Suppressor Proteins; C440808:PINX1 protein, human; C104342:TEP1 protein, human; C422952:telomerase RNA; C418109:TNKS protein, human