Caslini Corrado, Serna Amparo
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
Biomedicines. 2023 Mar 16;11(3):925. doi: 10.3390/biomedicines11030925.
Telomere transcription into telomeric repeat-containing RNA (TERRA) is an integral component of all aspects of chromosome end protection consisting of telomerase- or recombination-dependent telomere elongation, telomere capping, and the preservation of the (sub)telomeric heterochromatin structure. The chromatin modifier and transcriptional regulator MLL binds to telomeres and regulates TERRA transcription in telomere length homeostasis and response to telomere dysfunction. MLL fusion proteins (MLL-FPs), the product of rearrangements in leukemia, also bind to telomeric chromatin. However, an effect on telomere transcription in -rearranged (-r) leukemia has not yet been evaluated. Here, we show increased UUAGGG repeat-containing RNA levels in -r acute lymphoblastic leukemia (ALL) when compared to non--r ALL and myeloid leukemia. rearrangements do not affect telomere length and UUAGGG repeat-containing RNA levels correlate with mean telomere length and reflect increased levels of TERRA. Furthermore, high levels of TERRA in -r ALL occur in the presence of telomerase activity and are independent of ploidy, an underestimated source of variation on the overall transcriptome size in a cell. This rearrangement-dependent and lymphoid lineage-associated increase in levels of TERRA supports a sustained telomere transcription by MLL-FPs that correlates with marked genomic stability previously reported in pediatric -r ALL.
端粒转录生成含端粒重复序列的RNA（TERRA）是染色体末端保护各个方面的一个组成部分，这些方面包括端粒酶或重组依赖性端粒延长、端粒封端以及（亚）端粒异染色质结构的维持。染色质修饰剂和转录调节因子MLL与端粒结合，并在端粒长度稳态和对端粒功能障碍的反应中调节TERRA转录。MLL融合蛋白（MLL-FPs）是白血病中重排的产物，也与端粒染色质结合。然而，其对重排（-r）白血病中端粒转录的影响尚未得到评估。在这里，我们发现与非-r急性淋巴细胞白血病（ALL）和髓系白血病相比，-r急性淋巴细胞白血病中含UUAGGG重复序列的RNA水平升高。重排不影响端粒长度，且含UUAGGG重复序列的RNA水平与平均端粒长度相关，并反映出TERRA水平升高。此外，-r ALL中高水平的TERRA在端粒酶活性存在的情况下出现，且与倍性无关，倍性是细胞中整体转录组大小变化的一个被低估的来源。这种重排依赖性和淋巴细胞系相关的TERRA水平升高支持了MLL-FPs持续的端粒转录，这与先前报道的儿童-r ALL中显著的基因组稳定性相关。
