The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia
The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia
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形态学诊断儿童急性早幼粒细胞白血病的遗传学及临床特征
DOI：
10.1038/s41375-018-0338-z
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发表时间：
2019-06-01
期刊：
影响因子：
11.4
通讯作者：
Li, Ben-Shang
中科院分区：
文献类型：
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作者：
Zhao, Jie;Liang, Jian-Wei;Li, Ben-Shang
急性早幼粒细胞白血病(APL)以t(15；17)(q22；q21)为特征，导致APML-RARA融合，是APL的主要驱动因素。少数用常规方法(核型分析、FISH和RT-PCR)不能确定的PML-RARA病例涉及在形态、细胞化学和免疫表型上与APL完全一致的异常早幼粒细胞。为了探讨APL的发病机制和复发机制，我们对111例APL患儿进行了下一代测序的综合变异分析。对120例初诊和复发期DNA标本进行结构变异(SV)分析，发现RARA重排95例(其中PML-RARA 94例，NPM-RARA 1例)，KMT2重排2例。在确诊时未发现任何RARA重排的13例RNA样本中，发现CPSF6-RARG、NPM1-CCDC28A和TBC1D15-RAB21各1例，以及2例TBL1XR1-RARB融合。这些未发现的融合基因强烈提示，它们在白血病发生中的作用可能是由于参与视黄醇信号转导的核受体超家族(RARBorRARG)的其他成员的异常，甚至可能是由于与异常的视黄酸受体的形成不同的机制引起的。对77例(80例)RARA重排患儿进行单核苷酸变异(SNV)分析，发现原发APL基因在FLT3、WT1、USP9X、NRAS和ARID1A发生了反复突变，其中WT1为复发APL中唯一的重复突变基因，WT1、NPM1、NRAS、Flt3和NSD1在17例未发生RARA重排的初发样本中重复突变，9例复发样本中WT1、NPM1、TP53和RARA重复突变。有RARA重排的APL的存活率明显好于无RARA重排的APL。因此，形态诊断为APL但不能确定有aRARA重排的患者更合理地被归类为APL以外的AML亚类，并应根据基因异常考虑个体化治疗。
Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q22;q21), resulting in aPML-RARAfusion that is the master driver of APL. A few cases that cannot be identified withPML-RARAby using conventional methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis by next-generation sequencing in 111 pediatric patients morphologically diagnosed as APL. Structural variant (SV) analysis in 120 DNA samples from both diagnosis and relapse stage identified 95 samples withRARArearrangement (including 94 withPML-RARAand one withNPM-RARA) and two samples withKMT2Arearrangement. In the eligible 13 RNA samples without anyRARArearrangement at diagnosis, one case each withCPSF6-RARG,NPM1-CCDC28A, andTBC1D15-RAB21and two cases with aTBL1XR1-RARBfusion were discovered. These uncovered fusion genes strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype may arise by abnormalities of other members of the nuclear receptor superfamily involved in retinoid signaling (RARBorRARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Single-nucleotide variant (SNV) analysis in 77 children (80 samples) withRARArearrangement showed recurrent alternations of primary APL inFLT3,WT1,USP9X,NRAS, andARID1A, with a strong potential for involvement in pathogenesis, andWT1as the only recurrently mutated gene in relapsed APL.WT1,NPM1,NRAS,FLT3, andNSD1were identified as recurrently mutated in 17 primary samples withoutRARArearrangement andWT1,NPM1,TP53, andRARAas recurrently mutated in 9 relapsed samples. The survival of APL withRARArearrangement is much better than withoutRARArearrangement. Thus, patients morphologically diagnosed as APL that cannot be identified as having aRARArearrangement are more reasonably classified as a subclass of AML other than APL, and individualized treatment should be considered according to the genetic abnormalities.