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DNA依赖蛋白激酶催化亚基（DNA-PKcs）的非同源末端连接（NHEJ）活性失活可防止范可尼贫血前白血病造血干细胞（HSC）的扩增。

Inactivation of the NHEJ Activity of DNA-PKcs Prevents Fanconi Anemia Pre-Leukemic HSC Expansion.

作者信息

Chatla Srinivas, Wilson Andrew F, Pang Qishen

机构信息

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

出版信息

Int J Stem Cells. 2019 Nov 30;12(3):457-462. doi: 10.15283/ijsc19074.

DOI:10.15283/ijsc19074
PMID:31474030
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6881041/
Abstract

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and high risk of cancer particularly leukemia. Here we show that inactivation of the non-homologous end-joining (NHEJ) activity of DNA-PKcs prevented DNA damage-induced expansion of FA pre-leukemic hematopoietic stem cells (HSCs). Furthermore, we performed serial BM transplantation to demonstrate that the DNA damage-induced expanded FA HSC compartment contained pre-leukemic stem cells that required the NHEJ activity of DNA-PKcs to induce leukemia in the secondary recipients. These results suggest that NHEJ may collaborate with FA deficiency to promote DNA damage-induced expansion of pre-leukemic HSCs.

摘要

范可尼贫血（FA）是一种遗传性疾病，其特征为骨髓衰竭以及患癌尤其是白血病的高风险。在此我们表明，DNA依赖蛋白激酶催化亚基（DNA-PKcs）的非同源末端连接（NHEJ）活性失活可阻止DNA损伤诱导的FA白血病前期造血干细胞（HSC）扩增。此外，我们进行了连续骨髓移植，以证明DNA损伤诱导扩增的FA HSC区室含有白血病前期干细胞，这些干细胞需要DNA-PKcs的NHEJ活性才能在二级受体中诱发白血病。这些结果表明，NHEJ可能与FA缺陷协同作用，以促进DNA损伤诱导的白血病前期HSC扩增。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7663/6881041/47b692d04a6a/ijsc-12-457f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7663/6881041/7a44ab525833/ijsc-12-457f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7663/6881041/47b692d04a6a/ijsc-12-457f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7663/6881041/7a44ab525833/ijsc-12-457f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7663/6881041/47b692d04a6a/ijsc-12-457f2.jpg

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本文引用的文献

1
Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia.遗传性骨髓衰竭综合征范可尼贫血分子发病机制的最新发现。
Blood Rev. 2017 May;31(3):93-99. doi: 10.1016/j.blre.2016.10.002. Epub 2016 Oct 13.
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The immune receptor Trem1 cooperates with diminished DNA damage response to induce preleukemic stem cell expansion.免疫受体Trem1与减弱的DNA损伤反应协同作用，诱导白血病前期干细胞扩增。
Leukemia. 2017 Feb;31(2):423-433. doi: 10.1038/leu.2016.242. Epub 2016 Aug 29.
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Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells.
Cancer Cell Int. 2021 Oct 18;21(1):544. doi: 10.1186/s12935-021-02243-w.
高活性非同源末端连接选择了对合成致死具有抗性的病理性范可尼贫血造血干细胞和祖细胞。
Sci Rep. 2016 Feb 26;6:22167. doi: 10.1038/srep22167.
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Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics.范可尼贫血：用于人类遗传学和先进治疗学研究的模型疾病。
Curr Opin Genet Dev. 2015 Aug;33:32-40. doi: 10.1016/j.gde.2015.07.002. Epub 2015 Aug 6.
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Fanconi anaemia: genetics, molecular biology, and cancer – implications for clinical management in children and adults.范科尼贫血：遗传学、分子生物学与癌症——对儿童及成人临床管理的启示
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Fanconi anaemia and the repair of Watson and Crick DNA crosslinks.范可尼贫血症与沃森-克里克 DNA 交联的修复。
Nature. 2013 Jan 17;493(7432):356-63. doi: 10.1038/nature11863.
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Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair.DNA-PKcs 突变小鼠的先天性骨髓衰竭与 DNA 修复缺陷有关。
J Cell Biol. 2011 Apr 18;193(2):295-305. doi: 10.1083/jcb.201009074. Epub 2011 Apr 11.
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Dangerous liaisons: Fanconi anemia and toxic nonhomologous end joining in DNA crosslink repair.危险的勾结：范可尼贫血症与非同源末端连接在 DNA 交联修复中的毒性作用。
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Mol Cell. 2010 Jul 9;39(1):25-35. doi: 10.1016/j.molcel.2010.06.026.