TERRA（含端粒重复序列的 RNA）在急性髓系白血病中失调。
TERRA (telomeric repeat-containing RNA) is dysregulated in acute myeloid leukemia.
发表日期：2023 Sep 29
作者：
Luiz Fernando B Catto, Leonardo C Zanelatto, Flavia Donaires, Vinicius S Carvalho, Barbara A Santana, André Luiz Pinto, Daianne Maciely Carvalho Fantacini, Lucas E B Souza, Natasha P Fonseca, Bruno S Telho, Maria Isabel Ayrosa Madeira, Katia B B Pagnano, Ana Beatriz Gloria, Evandro M Fagundes, Marcia Higashi, Elenaide C Nunes, Fabiola Traina, Lorena Lobo de Figueiredo-Pontes, Eduardo M Rego, Rodrigo T Calado
来源：
Blood Advances
摘要：
TERRA（含端粒重复的RNA）是一类从亚端粒和端粒区域转录的长非编码RNA。 TERRA 与亚端粒和端粒 DNA 结合，形成 R 环（DNA-RNA 杂合体），参与端粒维持和端粒酶功能，但 TERRA 在人类细胞中的作用尚不清楚。在这里，我们首次全面研究了急性髓系白血病（AML）、急性淋巴细胞白血病（ALL）、端粒生物学障碍（TBD）患者和健康受试者探索性队列中原代人类造血细胞中的 TERRA 表达。 TERRA 表达在原代人类造血细胞中受到抑制，包括健康供体、ALL 和 TBD，无论其端粒长度如何（AML 除外）。由 88 名 AML 患者组成的第二个队列显示，TERRA 在 AML 亚组中过度表达，其特征还包括较高的 R 环形成、较低的 TERT 和 RNAseH2 表达以及缺乏体细胞剪接因子突变。端粒长度与 TERRA 表达水平不相关。为了评估 TERRA R 环在 AML 中的作用，我们通过增加两种 AML 细胞系中 RNAseH1 的表达来诱导 R 环耗竭。 AML 细胞系中 TERRA R 环的减少导致对阿糖胞苷的化疗敏感性增加。我们的研究结果表明，TERRA 在原代人类造血细胞中受到一致抑制，但在端粒酶较低的 AML 亚群中异常表达。版权所有 © 2023 美国血液学会。
TERRA (telomeric repeat-containing RNA) is a class of long non-coding RNAs transcribed from subtelomeric and telomeric regions. TERRA binds to the subtelomeric and telomeric DNA forming R-loops (DNA-RNA hybrids), which are involved in telomere maintenance and telomerase function, but the role of TERRA in human cells is not well characterized. Here, we comprehensively investigated for the first time TERRA expression in primary human hematopoietic cells from an exploratory cohort of patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), telomere-biology disorder (TBD), and healthy subjects. TERRA expression was repressed in primary human hematopoietic cells, including healthy donors, ALL, and TBD, irrespective of their telomere length, except for AML. A second cohort composed of 88 AML patients showed that TERRA was overexpressed in an AML subgroup also characterized by higher R-loop formation, low TERT and RNAseH2 expression, and a paucity of somatic splicing factor mutations. Telomere length did not correlate with TERRA expression levels. To assess the role of TERRA R-loops in AML, we induced R-loops depletion by increasing RNAseH1 expression in two AML cell lines. Decreased TERRA R-loops in AML cell lines resulted in increased chemosensitivity to cytarabine. Our findings indicate that TERRA is uniformly repressed in primary human hematopoietic cells, but abnormally expressed in an AML subset with low telomerase.Copyright © 2023 American Society of Hematology.