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

Abstract

Telomeres and telomerase are closely linked to uncontrolled cellular proliferation, immortalization and carcinogenesis. Telomerase has been largely studied in the context of cancer, including leukemias. Deregulation of human telomerase gene hTERT is a well-established step in leukemia development. B-acute lymphoblastic leukemia (B-ALL) recovery rates exceed 90% in children; however, the relapse rate is around 20% among treated patients, and 10% of these are still incurable. This review highlights the biological and clinical relevance of telomerase for B-ALL and the implications of its canonical and non-canonical action on signaling pathways in the context of disease and treatment. The physiological role of telomerase in lymphocytes makes the study of its biomarker potential a great challenge. Nevertheless, many works have demonstrated that high telomerase activity or hTERT expression, as well as short telomeres, correlate with poor prognosis in B-ALL. Telomerase and related proteins have been proven to be promising pharmacological targets. Likewise, combined therapy with telomerase inhibitors may turn out to be an alternative strategy for B-ALL.

Keywords: acute leukemia; hTERT; leukemia; telomerase; telomere.

Figure 1

Telomerase representation. Dyskerin complex (NHP2, NOP10 and DKC) binds to hTR through its ACA domain. TCAB1 binds to TERT and to hTR. The template region of hTR binds to the telomeric 3′ -end strand. Shelterin binds to telomeric repeat region. TRF2 interacts with RAP1 and TRF1, binding directly to the telomeric DNA and to TIN2, which also binds to TPP1. TPP1 interacts with POT1, which is responsible for recruiting telomerase to telomeres through the TEN domain of TERT.

Figure 2

Model of telomere regulation in B cells. The green color represents telomere length and the blue color the chromosomes. The germinal center has greater telomere length than naive and memory cells.