Impact of germline <i><scp>CTC</scp>1</i> alterations on telomere length in acquired bone marrow failure

Shen, Wenyi; Kerr, Cassandra M; Przychozen, Bartlomiej; Mahfouz, Reda Z.; LaFramboise, Thomas; Nagata, Yasunobu; Hanna, Rabi; Radivoyevitch, Tomas; Nazha, Aziz; Sekeres, Mikkael A.; Maciejewski, Jaroslaw P.

doi:10.1111/bjh.15862

Cited by 11 publications

(9 citation statements)

References 13 publications

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“…DC genes function in telomere maintenance; CTC1 functions in a telomere-associated complex to protect the telomere from lethal DNA degradation 16 . Although these DC genes have autosomal recessive inheritance, an association between monoallelic deleterious germline mutations and myeloid malignancies has been reported 17 .…”

Section: Resultsmentioning

confidence: 99%

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

Kim

Yun

Lee

et al. 2020

Sci Rep

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Acute myeloid leukemia (AML) is one of the most common types of leukemia. With the recent advances in sequencing technology and the growing body of knowledge on the genetics of AML, there is increasing concern about cancer predisposing germline mutations as well as somatic mutations. As familial cases sharing germline mutations are constantly reported, germline predisposition gene mutations in patients with AML are gaining attention. We performed genomic sequencing of Korean patients diagnosed with AML to identify the prevalence and characteristics of germline predisposition mutations. Among 180 patients, germline predisposition mutations were identified in 13 patients (13/180, 7.2%, eight adults and five children). Germline mutations of BLM,

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Section: Resultsmentioning

confidence: 99%

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

Kim

Yun

Lee

et al. 2020

Sci Rep

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“…Germline CTC1 mutation has also been observed in DC and acquired bone marrow failure patients (Shen et al, 2019). DC is a rare inherited bone marrow failure disorder caused by aberrant telomere shortening.…”

Section: Discussionmentioning

confidence: 99%

miR-376a Provokes Rectum Adenocarcinoma Via CTC1 Depletion-Induced Telomere Dysfunction

Yang

Zhao

Wang

et al. 2021

Front. Cell Dev. Biol.

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CTC1 is a component of the mammalian CST (CTC1–STN1–TEN1) complex which plays essential roles in resolving replication problems to facilitate telomeric DNA and genomic DNA replication. We previously reported that the depletion of CTC1 leads to stalled replication fork restart defects. Moreover, the mutation in CTC1 caused cancer-prone diseases including Coats plus (CP) or dyskeratosis congenita (DC). To better understand the CTC1 regulatory axis, the microRNAs (miRNAs) targeting to CTC1 were predicted by a bioinformatics tool, and the selected candidates were further confirmed by a dual-luciferase reporter assay. Here, our current results revealed that miR-376a significantly reduced CTC1 expression at the transcription level by recognizing CTC1 3′-UTR. In addition, the overexpression of miR-376a induced telomere replication defection and resulted in direct replicative telomere damage, which could be rescued by adding back CTC1. Telomere shortening was also observed upon miR-376a treatment. Furthermore, for the clinical patient samples, the high expression of miR-376a was associated with the deregulation of CTC1 and a poor outcome for the rectum adenocarcinoma patients. Together, our results uncovered a novel role of miR-376a in stimulating rectum adenocarcinoma progression via CTC1 downregulating induced telomere dysfunction.

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“…The marrow from patients with GATA2 deficiency is typically hypocellular, with varying degrees of dysplasia, atypical megakaryocytes and abnormal cytogenetics, particularly monosomy 7 and trisomy 8 72 . More recently, a growing list of germline mutations has been associated with marrow failure, such as of MDM4 , DADA2 , CTC1 , MECOM and SAMD9L 73–77 …”

Section: Pathogenesismentioning

confidence: 99%

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries

Scheinberg

2021

Br J Haematol

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The progress in aplastic anaemia (AA) management is one of success. Once an obscure entity resulting in death in most affected can now be successfully treated with either haematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). The mechanisms that underly the diminution of haematopoietic stem cells (HSCs) are now better elucidated, and include genetics and immunological alterations. Advances in supportive care with better antimicrobials, safer blood products and iron chelation have greatly impacted AA outcomes. Working somewhat 'mysteriously', anti-thymocyte globulin (ATG) forms the base for both HSCT and IST protocols. Efforts to augment immunosuppression potency have not, unfortunately, led to better outcomes. Stimulating HSCs, an often-sought approach, has not been effective historically. The thrombopoietin receptor agonists (Tpo-RA) have been effective in stimulating early HSCs in AA despite the high endogenous Tpo levels. Dosing, timing and best combinations with Tpo-RAs are being defined to improve HSCs expansion in AA with minimal added toxicity. The more comprehensive access and advances in HSCT and IST protocols are likely to benefit AA patients worldwide. The focus of this review will be on the medical treatment advances in AA.

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Impact of germline CTC1 alterations on telomere length in acquired bone marrow failure

Cited by 11 publications

References 13 publications

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

Prevalence and clinical implications of germline predisposition gene mutations in patients with acute myeloid leukemia

miR-376a Provokes Rectum Adenocarcinoma Via CTC1 Depletion-Induced Telomere Dysfunction

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries

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