儿童急性髓样白血病中NUP98融合的分子和临床特征的全面描述。
Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia.
发表日期：2023 Feb 23
作者：
Eline J M Bertrums, Jenny L Smith, Lauren Harmon, Rhonda E Ries, Yi-Cheng J Wang, Todd A Alonzo, Andrew J Menssen, Karen M Chisholm, Amanda R Leonti, Katherine Tarlock, Fabiana Ostronoff, Era L Pogosova-Agadjanyan, Gertjan J L Kaspers, Henrik Hasle, Michael Dworzak, Christiane Walter, Nora Muhlegger, Cristina Morerio, Laura Pardo, Betsy Hirsch, Susana Raimondi, Todd M Cooper, Richard Aplenc, Alan S Gamis, Edward A Kolb, Jason E Farrar, Derek Stirewalt, Xiaotu Ma, Tim I Shaw, Scott N Furlan, Lisa Eidenschink Brodersen, Michael R Loken, Marry M Van den Heuvel-Eibrink, C Michel Zwaan, Timothy J Triche, Bianca F Goemans, Soheil Meshinchi
来源：
HAEMATOLOGICA
摘要：
NUP98融合体是AML中一类罕见的复发性改变家族，与不良结局有关。为了确定这类融合体的潜在生物学和临床影响，我们对2235名AML儿童和年轻成人进行全面的转录组、表观基因组和免疫表型分析，并鉴定了160个NUP98重排（7.2%），其中包括108个NUP98-NSD1（4.8%），32个NUP98-KDM5A（1.4%）和20个NUP98-X案例（0.9%），涉及13个不同的融合伙伴。融合伙伴决定了疾病特征和生物学，患有NUP98-NSD1或NUP98-KDM5A的患者具有独特的免疫表型、转录组和表观基因组特征。与两种最常见的NUP98融合体不同，NUP98-X变异通常不是隐性的。此外，NUP98-X案例伴有WT1突变，并具有类似于NUP98-NSD1或NUP98-KDM5A的表观基因组特征。合作的FLT3-ITD和WT1突变定义了NUP98-NSD1，而13号染色体异常在NUP98-KDM5A中高度富集。重要的是，我们证明，除了携带异常chr13的患者外，在总体生存方面，NUP98融合体预示着可怕的结局。
NUP98 fusions c omprise a family o f rare r ecurrent a lterations i n A ML, associated w ith adverse outcomes. To define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98- NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chr13.