TY - JOUR
T1 - Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia
AU - Bertrums, Eline J. M.
AU - Smith, Jenny L.
AU - Harmon, Lauren
AU - Ries, Rhonda E.
AU - Wang, Yi-Cheng J.
AU - Alonzo, Todd A.
AU - Menssen, Andrew J.
AU - Chisholm, Karen M.
AU - Leonti, Amanda R.
AU - Tarlock, Katherine
AU - Ostronoff, Fabiana
AU - Pogosova-Agadjanyan, Era L.
AU - Kaspers, Gertjan J. L.
AU - Hasle, Henrik
AU - Dworzak, Michael
AU - Walter, Christiane
AU - Mühlegger, Nora
AU - Morerio, Cristina
AU - Pardo, Laura
AU - Hirsch, Betsy
AU - Raimondi, Susana
AU - Cooper, Todd M.
AU - Aplenc, Richard
AU - Gamis, Alan S.
AU - Kolb, Edward A.
AU - Farrar, Jason E.
AU - Stirewalt, Derek
AU - Ma, Xiaotu
AU - Shaw, Tim I.
AU - Furlan, Scott N.
AU - Brodersen, Lisa Eidenschink
AU - Loken, Michael R.
AU - van den Heuvel-Eibrink, Marry M.
AU - Zwaan, C. Michel
AU - Triche, Timothy J.
AU - Goemans, Bianca F.
AU - Meshinchi, Soheil
N1 - Funding Information: This work was supported by the following NIH/NCI/NCTN grant awards: RO1CA190661, R01CA160872, R01AI171984, U10CA180888, U10CA180819, and U24CA196175, U10CA180886, U10CA180899, St. Baldricks Foundation, the Rally Foundation, and the Michelle Lunn Hope Foundation. This content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: ©2023 Ferrata Storti Foundation.
PY - 2023/8/1
Y1 - 2023/8/1
N2 - NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order 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 chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).
AB - NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order 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 chromosome 13 (clinicaltrials gov. Identifiers: NCT00002798, NCT00070174, NCT00372593, NCT01371981).
UR - http://www.scopus.com/inward/record.url?scp=85161878773&partnerID=8YFLogxK
U2 - https://doi.org/10.3324/haematol.2022.281653
DO - https://doi.org/10.3324/haematol.2022.281653
M3 - Article
C2 - 36815378
SN - 0390-6078
VL - 108
SP - 2044
EP - 2058
JO - Haematologica
JF - Haematologica
IS - 8
ER -