Mechanism of Human Telomerase Reverse Transcriptase (hTERT) Regulation and Clinical Impacts in Leukemia

Abstract

The proliferative capacity and continuous survival of cells are highly dependent on telomerase expression and the maintenance of telomere length. For this reason, elevated expression of telomerase has been identified in virtually all cancers, including leukemias; however, it should be noted that expression of telomerase is sometimes observed later in malignant development. This time point of activation is highly dependent on the type of leukemia and its causative factors. Many recent studies in this field have contributed to the elucidation of the mechanisms by which the various forms of leukemias increase telomerase activity. These include the dysregulation of telomerase reverse transcriptase (TERT) at various levels which include transcriptional, post-transcriptional, and post-translational stages. The pathways and biological molecules involved in these processes are also being deciphered with the advent of enabling technologies such as next-generation sequencing (NGS), ribonucleic acid sequencing (RNA-Seq), liquid chromatography-mass spectrometry (LCMS/MS), and many others. It has also been established that TERT possess diagnostic value as most adult cells do not express high levels of telomerase. Indeed, studies have shown that prognosis is not favorable in patients who have leukemias expressing high levels of telomerase. Recent research has indicated that targeting of this gene is able to control the survival of malignant cells and therefore offers a potential treatment for TERT-dependent leukemias. Here we review the mechanisms of hTERT regulation and deliberate their association in malignant states of leukemic cells. Further, we also cover the clinical implications of this gene including its use in diagnostic, prognostic, and therapeutic discoveries.

The Relevance of Telomerase and Telomere-Associated Proteins in B-Acute Lymphoblastic Leukemia

“…The multi-functional profile of telomerase, as well as its relevance for carcinogenesis and cancer maintenance, make it an extremely relevant target for the development of studies focusing on both therapeutical purposes and on the understanding of tumor biology, especially in blood-related diseases [ 167 , 168 , 169 ].…”

Telomerase-targeted therapies in myeloid malignancies

“…TERT activity is highly regulated through transcriptional, posttranscriptional, and posttranslational mechanisms. 29 …”

The Role of WRAP53 in Cell Homeostasis and Carcinogenesis Onset

“…Evaluation of telomerase activity, together with the integrity of the telomeres, has emerged as an important prognostic toll in hematological cancers [ 86 , 87 , 88 ]. The genomic instability in leukemia derived from telomere disorders is one of the major factors responsible for acquired therapeutic resistance due to karyotype abnormalities and activation of the cell pathways that allow for an escape of the proposed therapeutic mechanisms [ 89 , 90 , 91 , 92 ].…”