Blood:家族性B细胞前体-急性淋巴细胞白血病的胚系PAX5突变

2020-10-10 星云 MedSci原创

近年来,通过全基因组测序分析,已有大量令人信服的证据证明遗传易感性在儿童B细胞前体-急性淋巴细胞白血病(BCP-ALL)中的作用是由PAX5基因突变引起的。

近年来,通过全基因组测序分析,已有大量令人信服的证据证明遗传易感性在儿童B细胞前体-急性淋巴细胞白血病(BCP-ALL)中的作用是由PAX5基因突变引起的。

PAX5基因的一个影响八肽结构域的复发性突变,p.Gly183Ser在三个不相关的家系中被报道,而影响DNA结合配对结构域的p.Arg38His突变在另一个家系中被报道。

在本研究中,Duployez等在一个有三个孩子罹患BCP-ALL的家系中检测到了PAX5 p.Arg38His突变,以此加强了家族性BCP-ALL遗传特征的假设。其中一患儿在初诊两年后复发,并接受了其兄弟的造血干细胞进行了同种异体移植;其兄弟后来也确诊为BCP-ALL。该患儿后来又从移植的细胞中复发。

通过小鼠同基因移植发现,与野生型PAX5挽救的Pax5-/-pro-B细胞不同,p.Arg38His的表达不会破坏转导的Pax5-/-pro-B细胞的植入能力,并且可以使个体对BCP-ALL易感。

通过功能和分子分析,研究人员证明了p.Arg38His作为一个亚型变异体改变了PAX5靶基因的表达模式。这些数据强调了转录失调的重要性,特别是在家族性BCP-ALL中涉及B细胞分化的基因。

综上,本研究证明,BCP-ALL易感性的遗传基础被低估了,应该在进行任何家族性同种异体移植之前多加以考虑。

原始出处:

Nicolas Duployez, et al. Germline PAX5 mutation predisposes to familial B acute lymphoblastic leukemia. Blood. October 9, 2020.

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