Background

Only rare cases of acute myeloid leukemia (AML) have been shown to harbor a t(8;11)(p11.2;p15.4). This translocation is believed to involve the fusion of NSD3 or FGFR1 with NUP98; however, apart from targeted mRNA quantitative PCR analysis, no molecular approaches have been utilized to define the chimeric fusions present in these rare cases.

Case Presentation

Here we present the case of a 51-year-old female with AML with myelodysplastic-related morphologic changes, 13q deletion and t(8;11), where initial fluorescence in situ hybridization (FISH) assays were consistent with the presence of NUP98 and FGFR1 rearrangements, and suggestive of NUP98/FGFR1 fusion. Using a streamlined clinical whole-genome sequencing approach, we resolved the breakpoints of this translocation to intron 4 of NSD3 and intron 12 of NUP98, indicating NUP98/NSD3 rearrangement as the likely underlying aberration. Furthermore, our approach identified small variants in WT1 and STAG2, as well as an interstitial deletion on the short arm of chromosome 12, which were cryptic in G-banded chromosomes.

Conclusions

NUP98 fusions in acute leukemia are predictive of poor prognosis. The associated fusion partner and the presence of co-occurring mutations, such as WT1, further refine this prognosis with potential clinical implications. Using a clinical whole-genome sequencing analysis, we resolved t(8;11) breakpoints to NSD3 and NUP98, ruling out the involvement of FGFR1 suggested by FISH while also identifying multiple chromosomal and sequence level aberrations.

中文翻译：

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临床全基因组测序和 FISH 在急性髓系白血病患者中鉴定出两种不同的 NUP98 融合伴侣：病例报告

背景

只有罕见的急性髓系白血病 (AML) 病例被证明存在于 (8;11)(p11.2;p15.4)。这种易位被认为涉及NSD3或FGFR1与NUP98的融合；然而，除了靶向 mRNA 定量 PCR 分析之外，还没有利用任何分子方法来定义这些罕见病例中存在的嵌合融合体。

案例展示

在这里，我们介绍了一名患有 AML 的 51 岁女性患者的病例，该患者患有骨髓增生异常相关的形态学变化、13q 缺失和 t(8;11)，其中初始荧光原位杂交 (FISH) 检测与NUP98和t(8;11 ) 的存在一致。FGFR1重排，提示NUP98/FGFR1融合。使用简化的临床全基因组测序方法，我们解决了这种易位到NSD3内含子 4 和NUP98内含子 12 的断点，表明NUP98 / NSD3重排可能是潜在的畸变。此外，我们的方法还发现了WT1和STAG2中的小变异，以及 12 号染色体短臂上的间质缺失，这些缺失在 G 带染色体中是隐秘的。

结论

急性白血病中的NUP98融合预示着不良预后。相关的融合伴侣和同时发生的突变（例如WT1）的存在，进一步改善了这种预后，具有潜在的临床意义。通过临床全基因组测序分析，我们解决了NSD3和NUP98的 t(8;11) 断点，排除了FISH 提示的FGFR1的参与，同时还鉴定了多个染色体和序列水平畸变。