Document Type

Article

Publication Date

8-1-2023

Identifier

DOI: 10.3324/haematol.2022.281653; PMCID: PMC10388277

Abstract

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).

Journal Title

Haematologica

Volume

108

Issue

8

First Page

2044

Last Page

2058

MeSH Keywords

Child; Young Adult; Humans; Leukemia, Myeloid, Acute; Mutation; Nuclear Pore Complex Proteins; Gene Expression Profiling; Retinoblastoma-Binding Protein 2

Keywords

Acute Myeloid Leukemia; Mutation; Nuclear Pore Complex Proteins; Gene Expression Profiling; Retinoblastoma-Binding Protein 2

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