Increased expression of telomere length regulating factors TRF1, TRF2 and TIN2 in patients with adult T‐cell leukemia

Abstract

Here, we report that freshly isolated unstimulated adult T-cell leukemia (ATL) cells present high telomerase activity compared to asymptomatic carriers or normal donors. In spite of this high telomerase activity, ATL cells retained shorter telomeres compared to those of uninfected cells isolated from the same patients. Because the safeguarding of telomere length is critical to the unlimited proliferation of tumor cells, we investigated the underlying mechanism for short telomere maintenance in ATL cells. Transcriptional and posttranscriptional expression of telomere-binding proteins TRF1, TRF2, TIN2 and POT1, known to regulate telomere homeostasis and protection, were evaluated. We found that TRF1 and TRF2 are overexpressed in in vivo patient's samples from ATL but not asymptomatic carriers, while levels of POT1 expression did not specifically increase in ATL. To gain insights into the regulation of TRF genes in HTLV-I infected cells, we investigated the expression of TIN2, a regulator of these genes, and found an increase in TIN2 expression in ATL patients. Together our results underscore the importance of telomerase and telomere length regulating factors as novel markers for ATL disease progression and as potential therapeutic targets for the treatment of HTLV-I-associated malignancies. ' 2006 Wiley-Liss, Inc.Key words: HTLV-I; ATL; telomerase; telomere; TRF1; leukemia Human T-cell leukemia virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia/lymphoma (ATL), an aggressive and fatal lymphoproliferative disorder.1,2 The poor prognosis of ATL patients is associated with the resistance of neoplastic cells to the conventional combination of high-dose chemotherapy and radiotherapy. 3 The mechanism by which HTLV-I engenders ATL is not clear, but the long latency period of several decades, preceding the disease, suggests that it relies upon long term survival and proliferation of virus-infected cells. [4][5][6] In fact, previous studies have shown that proliferation of ATL cells occurs mainly by replication of infected cells, leading to oligoclonal or monoclonal expansion.4-6 HTLV-I has evolved regulatory mechanisms to usurp cell cycle checkpoints 7-12 and apoptosis regulators, [13][14][15][16][17] and infected cells may escape from immune defenses, using a combinatorial effect of the regulatory proteins p30 and p12 that reduce viral expression and downregulate major histocompatibility complex expression, respectively. 18,19The DNA polymerase is unable to replicate telomeric structures, and thus each cellular division results in a progressive shortening of the telomere length. While telomere shortening may be associated with increased chromosomal instability and may facilitate carcinogenesis, it can also lead to irreversible senescence. Although in most cancer cells avoidance of telomere shortening beyond a critical size requires reactivation of telomerase expression, the sole expression of telomerase may not be sufficient for telomere elongation because of the ''open or closed'' nature of the telo...

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

“…Dysfunctional telomeres may arise either from critically short telomeres or by disruption of the shelterin complex [28]. In some hematologic malignancies, altered expression of shelterin proteins might disrupt the telomere structure, contributing to malignant transformation [13,[28][29][30][31]. Particularly in MCL, to our knowledge, there is only one report on the expression levels of TRF1, TRF2, TNKS, and PIF1 in a limited number of patients (7-8 cases) [30] and no differences in gene expression were found in comparison to lymph nodes.…”

Human T-cell Leukemia Virus Type I p30 Nuclear/Nucleolar Retention Is Mediated through Interactions with RNA and a Constituent of the 60 S Ribosomal Subunit

“…HTLV-I has evolved multiple strategies to prevent apoptosis and to extend the life span of infected cells (23)(24)(25)(26)(27). In turn, this allows accumulation of genetic mutations and disease progression.…”

Telomere dysfunction and its role in haematological cancer

“…A year later, Bellon et al (2006) reported that TL measured by Q-FISH was shortened in adult T-cell leukaemia/lymphoma. They further showed that TA was significantly increased though they postulated that this increase did not result in longer TL due to overexpression of TERF1, TERF2 and POT1, shelterin proteins that regulate the recruitment of telomerase at the terminus (Bellon et al, 2006).…”