NUP98‐NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia

Abstract

The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.

The Role of Nuclear Receptor–Binding SET Domain Family Histone Lysine Methyltransferases in Cancer

“…This recurrent translocation at t(5;11)(q35;p15.5) contains the FG-repeat domain of NUP98, a nucleoporin protein family member that can interact with the histone acetyltransferase CBP/p300 and the C-terminal of NSD1 that retains the five PHD fingers, the Cys-His rich domain (C5HCH), one PWWP domain, and the catalytic SET domain. NUP98-NSD1 is the most frequent (4%–5% of cases) fusion reported in pediatric AML and is associated with poor prognosis (Shiba et al 2013). Retroviral infection of NUP98-NSD1 enhanced expression of HoxA7, HoxA7, HoxA9, and Meis1 proto-oncogenes (Wang et al 2007).…”

A critical review of which children with acute myeloid leukaemia need stem cell procedures

“…NUP98 / NSD1 fusion due to the cryptic t(5;11)(q35;p15) occurs in almost 20% of children with cytogenetic normal AML (Hollink et al , ) and is often associated with FLT3 ‐internal tandem duplication (ITD) and a very poor outcome and salvage rate (Shiba et al , ). The data on HSCT in NUP98 / NSD1 are very sparse but suggest a benefit of HSCT in CR1 (Shiba et al , ).…”

NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report

“…[15][16][17][18] In recent studies analyzing the prevalence and clinical significance of NUP98/NSD1 in adult and pediatric AML patients, the investigators found that patients with NUP98/ NSD1 were more likely to also have FLT3/ITD. 11,[19][20][21][22] Despite the previous reported association between FLT3/ITD and NUP98/ NSD1, the prevalence and clinical significance of NUP98/NSD1 in FLT3/ITD AML have not yet been studied.…”