Comprehensive molecular and clinical characterization of <i>NUP98</i> fusions in pediatric acute myeloid leukemia

Abstract

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.

Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping

“…Bertrums et al recently identified 13 different fusion partners for NUP98 via transcriptome analysis in a cohort of 2235 children suffering from pediatric AML [45]. In total, at least 39 different fusion partners have been described to date, which can be subdivided into homeodomain (HD)-containing genes (at least 11 partners) and non-HD genes (at least 28 partners) [4,22,[45][46][47][48]. Intriguingly, ASH1L has not been detected as a fusion partner for NUP98 so far.…”

“…Of all 35 fusion partners mentioned in a review published in 2020 by Michmerhuizen et al, only the rare NUP98-fusions ::IQCG, ::RARG, and ::MLLT10 had DNA strand orientations that required a more complex genomic rearrangement than a single translocation or inversion, as shown for the novel NUP98::ASH1L [4, [77][78][79]. Two other exceptionally rare NUP98-fusions, namely ::BRWD3 and ::TAF3, also fell in this category [45][46][47]. The necessity of a more complex rearrangement in these cases with more than two chromosomal breakpoints might partially explain why NUP98::ASH1L has not been described before.…”

“…As the N-terminal region of NUP98, which is typically involved in these rearrangements, seems unlikely to be targetable, independent researchers sought to address the large group of variable C-terminal fusion partners [5,61,62]. A subset of non-HD NUP98 partners are associated with epigenetic regulation and show common features, such as SET-domains (ASH1L, KMT2A, NSD1, NSD3, SET, SETBP1), PHD-type zinc fingers (ASH1L, BPTF, JADE2, KDM5A, KMT2A, NSD1, NSD3, PHF23, TAF3), or bromo-domains (ASH1L, BPTF, BRWD3, KMT2A) [21,45,47,[63][64][65][66][67][68][69][70]. These may represent subgroups with distinct biological functions and are potentially directly targetable, as has been shown for the PHD of the NUP98::PHF23 oncoprotein in AML cell lines through disulfiram, a drug currently used for the treatment of chronic alcohol abuse, as it inhibits the PHD-containing acetaldehyde dehydrogenase needed for alcohol metabolism [71][72][73][74].…”

The landscape of NUP98 rearrangements clinical characteristics and treatment response from 1491 acute leukemia patients

“…It should be mentioned that NUP98::ASNSP4 as an unreported new fusion was just identified in a B-ALL patient (Table S1). It should also be mentioned that the partner gene of NUP98 in de novo AML was NSD1 (24), HOXA9 (9), PRRX2 (3), HMGB3 (2) and others (7), whereas in t-AML were NSD1 (1), HOXA9 (1) and TOP1 (1), and in s-AML were PRRX2 (1), KDM5A (1) and DDX10 (1) individually.…”

NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications

“…The NUP98 gene is rearranged with approximately 30 partners in AML (Table 1). NUP98::NSD1 and NUP98::KDM5A are frequently occurring NUP98 fusions in AML [30]. NUP98 gene alterations have been implicated in several hematological malignancies including AML, chronic myeloid leukemia (CML), juvenile myelomonocytic leukemia (JMML), T-cell acute lymphoblastic leukemia (T-ALL), and myelodysplastic syndrome (MDS) [26].…”