Yuen Lisa D, Hasserjian Robert P, Fathi Amir T, Luskin Marlise R, Winer Eric S, Dal Cin Paola, Kim Annette S, Lindsley R Coleman, Tsai Harrison K, Nardi Valentina
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA.
Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Cancer Center, Boston, MA.
Haematologica. 2025 Aug 14. doi: 10.3324/haematol.2025.288080.
Nucleoporin 98 rearrangements (NUP98r) are recurrent in myeloid neoplasms and are subtype-defining for acute myeloid leukemia (AML) in the World Health Organization Classification 5th edition (WHO5) and the International Consensus Classification (ICC). Identification of NUP98r is essential given frequency of treatment resistance and possibility of sensitivity to targeted therapies. However, NUP98r is often cryptic on karyotype and has over 40 described partners. Therefore, it is underdiagnosed in the absence of dedicated testing that is not routine at many practices, e.g. RNA-based next generation sequencing (NGS), NUP98 break-apart FISH, or RT-PCR for specific NUP98 fusions. Historically, AML with NUP98r has received the most attention in pediatric AML, where its incidence is highest, but has been increasingly characterized in adult AML. By contrast, the incidence and behavior of NUP98 fusions in myelodysplastic syndromes (MDS) is less understood and based predominantly on case reports. In this study, we describe our adult institutional experience with a clinically validated anchored multiplex PCR RNA-based targeted NGS assay, explore strategies for rational use of specific testing for NUP98r including a proof-of-principle based on WT1 and FLT3-ITD mutational status, and integrate our results with a review of the literature. In total, we identified 3 MDS and 15 AML patients with NUP98r as the genetic driver, including two novel fusion partners (FGF14 and LAMC3), thus highlighting the utility of NGS testing to detect NUP98 fusions. Recognition of NUP98r in myeloid neoplasms is crucial for accurate diagnosis and prognosis, with significant implications for therapy or enrollment in clinical trials.
核孔蛋白98重排（NUP98r）在髓系肿瘤中反复出现，在世界卫生组织第5版分类（WHO5）和国际共识分类（ICC）中是急性髓系白血病（AML）的亚型定义特征。鉴于治疗耐药的频率以及对靶向治疗敏感的可能性，NUP98r的鉴定至关重要。然而，NUP98r在核型上往往不明显，并且有超过40种已描述的伙伴基因。因此，在许多医疗机构没有进行常规的专门检测（例如基于RNA的下一代测序（NGS）、NUP98断裂分离荧光原位杂交（FISH）或针对特定NUP98融合的逆转录聚合酶链反应（RT-PCR））的情况下，它常常被漏诊。从历史上看，NUP98r阳性的AML在儿童AML中受到的关注最多，其发病率最高，但在成人AML中也越来越多地得到特征描述。相比之下，骨髓增生异常综合征（MDS）中NUP98融合的发病率和行为了解较少，主要基于病例报告。在本研究中，我们描述了我们成人机构使用经过临床验证的基于锚定多重PCR RNA的靶向NGS检测方法的经验，探索合理使用NUP98r特异性检测的策略，包括基于WT1和FLT3-ITD突变状态的原理验证，并将我们的结果与文献综述相结合。我们总共鉴定出3例MDS患者和15例以NUP98r为遗传驱动因素的AML患者，包括两个新的融合伙伴基因（FGF14和LAMC3），从而突出了NGS检测在检测NUP98融合中的实用性。在髓系肿瘤中识别NUP98r对于准确诊断和预后至关重要，对治疗或参加临床试验具有重要意义。
