Naive T-cells in myelodysplastic syndrome display intrinsic human telomerase reverse transcriptase (hTERT) deficiency.
Telomeres are specialized structures providing chromosome integrity during cellular division along with protection against premature senescence and apoptosis. Accelerated telomere attrition in patients with myelodysplastic syndrome (MDS) occurs by an undefined mechanism. Although the MDS clone originates within the myeloid compartment, T-lymphocytes display repertoire contraction and loss of naive T-cells. The replicative lifespan of T-cells is stringently regulated by telomerase activity. In MDS cases, we show that purified CD3+ T-cells have significantly shorter telomere length and reduced proliferative capacity upon stimulation compared with controls. To understand the mechanism, telomerase enzymatic activity and telomerase reverse transcriptase (hTERT), gene expression were compared in MDS cases (n=35) and healthy controls (n=42) within different T-cell compartments. Telomerase activity is greatest in naive T-cells illustrating the importance of telomere repair in homeostatic repertoire regulation. Compared with healthy controls, MDS cases had lower telomerase induction (P<0.0001) that correlated with significantly lower hTERT mRNA (P<0.0001), independent of age and disease stratification. hTERT mRNA deficiency affected naive but not memory T-cells, and telomere erosion in MDS occurred without evidence of an hTERT-promoter mutation, copy number variation or deletion. Telomerase insufficiency may undermine homeostatic control within the hematopoietic compartment and promote a change in the T-cell repertoire in MDS.
Immunology Program at the H Lee Moffitt Cancer Center, Tampa, FL, USA.
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Yang
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A
Mailloux
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DE
Rollison
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JS
Painter
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Maciejewski
R L
RL
Paquette
T P
TP
Loughran
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K
McGraw
H
H
Makishima
R
R
Radhakrishnan
S
S
Wei
X
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Ren
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Komrokji
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List
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Epling-Burnette
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001973:Bromodeoxyuridine; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere; D055815:Young Adult
C509186:TERT protein, human; D019098:Telomerase; D001973:Bromodeoxyuridine