Expression of non-coding telomeric RNA (TERRA) in acute leukemias and telomeropathies

Author(s)

Leonardo Campos Zanelatto

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2019-06-07

Examining board members

Rodrigo do Tocantins Calado de Saloma Rodrigues; Tiago Campos Pereira; Eduardo Magalhães Rego; Phillip Scheinberg

• Advisor: Rodrigo do Tocantins Calado de Saloma Rodrigues

Abstract

Telomeres are structures whose function is to protect the ends of the linear chromosomes and maintain genomic integrity. Constitutive mutations that interfere with telomere length maintenance mechanisms can lead to accelerated telomeric attrition, facilitating the emergence of various diseases, such as cancer. The telomeric repeat-containing RNA (TERRA), transcribed from the subtelomeric region of the chromosomes, may be related to telomerase activity and telomere length regulation, and changes in their expression levels have already been described in some types of cancers.This study aimed to investigate the expression of TERRA in peripheral blood and bone marrow of healthy individuals and patients with acute myeloid or lymphoid leukemias (AML or ALL), or telomeropathies (diseases that have in their core mutations in genes related to telomere biology). Also, the telomere length, the expression of TERT (one of the components of telomerase) and TRF2 (one of the accessory proteins that help to protect the telomere), telomerase activity and formation of RNA-DNA (R-loops) hybrids were evaluated. The AML (n=17) and telomeropathy (n=9) samples had a significantly decreased telomere length when compared to healthy subjects (p<0,0001 and p<0,001, respectively). AML and ALL (n=5) samples had high expression of TERT (p<0,001), TRF2 (p<0,05), and telomerase activity (p<0,0001), which was not observed in the telomeropathy samples. In addition, the AML samples displayed high TERRA transcription when compared to the healthy group for the four subtelomeric regions studied (p<0,001 for 20q, p<0,0001 for 10q, and p<0,01 for 15q and Xq/Yq), while ALL and telomeropathy samples displayed a heterogeneous expression, with levels close to those of the healthy group. Finally, AML and ALL samples showed an increase in TERRA R-loops formation (p<0.0001 and p<0.001, respectively) when compared to healthy individuals, which was not observed in telomeropathies (p>0,05). This is the first description of TERRA expression in normal and neoplastic human hematopoietic cells. Our results indicate that increased TERRA transcription is a characteristic of blasts in AML and not in cells with short telomeres. The expression of TERRA in the AMLs may contribute to the positive regulation of telomerase expression (TERT) as well as to its activity, which, together with the formation of TERRA R-loops, may help to maintain its shorter telomeres and prevent senescence (AU)

• FAPESP's process: 13/24199-0 - Evaluation of TERRA expression levels and its correlation with the telomeric imbalance in patients with hemopathies and telomeropathies.
• Grantee: Leonardo Campos Zanelatto
• Support Opportunities: Scholarships in Brazil - Doctorate