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Blood：TdT通过启动FLT3-ITD复制滑移促进AML

2019-10-21 QQY MedSci原创

TdTFLT3-ITDAMLN-核苷酸
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FLT3-ITDs (FLT3内部串联重复)是急性髓系白血病(AML)的预后驱动突变。虽然这些短重复突变发生在25%的AML患者中，但其形成的分子机制却仍不明确。了解FLT3-ITDs的起源将有助于我们进一步了解AML的起源。

FLT3-ITDs (FLT3内部串联重复)是急性髓系白血病(AML)的预后驱动突变。虽然这些短重复突变发生在25%的AML患者中，但其形成的分子机制却仍不明确。了解FLT3-ITDs的起源将有助于我们进一步了解AML的起源。

为了解析FLT3-ITDs的形成机制，研究人员分析了300个FLT3-ITDs的序列和分子解剖，包括114个在重复序列的两个重复拷贝之间有未知来源的额外的核苷酸的ITDs。

研究人员观察到了与重复滑移相一致的剖析现象，但仅1/3 FLT3-ITDs的滑移有种系微同源性(1-6 bp)参与。研究人员解释了通过神秘的微同源来解释大多数FLT3-ITDs中“缺失”微同源性的悖论：具体来说，是通过末端脱氧核苷酸转移酶(TdT)添加的非模板核苷酸(N-核苷酸)启动的。

研究人员认为，TdT介导的核苷酸添加超过了启动所需的量，从而在复制连接处产生N-区，可解释在这个位置观察到的额外核苷酸。FLT3-ITD N-区的G/C含量(66.9%)、二核苷酸组成和长度特征均与TdT合成一致。高TdT的AML的FLT3-ITDs发生率随之增加。

本研究结果揭示了淋巴样酶TdT在启动FLT3-ITDs中的作用。虽然TdT的生理作用是在IG/TCR基因V(D)J重组过程中通过增加N-核苷酸来增加抗原多样性，但本研究结果提示TdT活性异常对AML的发生有重要作用。

原始出处：

Julian Borrow， et al.Terminal Deoxynucleotidyl Transferase Promotes Acute Myeloid Leukemia By Priming FLT3-ITD Replication Slippage.Blood.2019001238. https：//doi.org/10.1182/blood.2019001238

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    2020-07-18 xiongke010

    #TdT#

    0

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    2019-10-23 kord1986

    #FLT3-ITD#

    0

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    2019-10-23 fengyi816

    #FLT3#

    0

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    2019-10-22 深海的鱼

    学习学习学习

    0

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    2019-10-22 147612bem32暂无昵称

    学习了

    0

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