NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern

Abstract

Translocations involving nucleoporin 98kD (NUP98) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML) but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/ NSD1 translocations in 3 of 92 cytogenetically normal (CN)-AML cases. To determine their exact frequency, we screened > 1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1-specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1-positive AML cases had significantly higher white blood cell counts (median, 147 ؋ 10 9 /L), more frequent FAB-M4/M5 morphology (in 63%), and more CN-AML (in 78%), FLT3/internal tandem duplication (in 91%) and WT1 mutations (in 45%) than NUP98/ NSD1-negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/ NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was < 10% for both pediatric and adult NUP98/NSD1-positive AML patients. NUP98/NSD1-positive AML showed a characteristic HOX-gene expression pattern, distinct from, for example, MLLrearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed. (Blood. 2011;118(13):3645-3656)

Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction

“…[19][20][21][22] In the present study, we provide experimental evidence that co-expression of NUP98-NSD1 and FLT3-ITD co-operate for transformation in vitro and the development of AML in vivo. In contrast, neither NUP98-NSD1 nor FLT3-ITD expression was able to induce the disease.…”

“…20,21 Interestingly, several reports have shown that the vast majority of NUP98-NSD1 positive patients also bear an FLT3-ITD mutation, suggesting functional co-operation. [19][20][21][22] Previous studies have shown that retroviral overexpression of NUP98-NSD1 alone is able to induce an AML-like disease in mice after a latency of several months. 23 Here we provide experimental evidence for a potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation for the transformation of murine hematopoietic cells in vitro and in vivo.…”

“…NUP98-NSD1 is the most frequent gene fusion in cytogenetically normal (CN) pediatric AML, and is generally associated with an aggressive disease and poor prognosis. [17][18][19] In adult AML patients, NUP98-NSD1 is rarely detected, but, if present, also confers a poor AML outcome. 20,21 Interestingly, several reports have shown that the vast majority of NUP98-NSD1 positive patients also bear an FLT3-ITD mutation, suggesting functional co-operation.…”

Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

“…This oncogenic fusion ( 12 ) is relatively common in cytogenetically normal pediatric AML ( 13,14 ), but relatively rare in adult AML ( 15 ). The NUP98 -NSD1 fusion was also detected in the diagnostic sample (600_0) and all follow-up samples, suggesting that this fusion was the initiating event in the development of the patient's disease.…”

Quantification of microRNA-181b in Egyptian Acute Myeloid Leukemia Patients and its Relation to Prognosis

“…They concluded that miRNA deregulation results in altered genetic expression and contributes to leukemogenesis in molecular high-risk CN-AML [1], [16] . Another interesting evidence supporting this relation was introduced by Hollink et al in 2011 [19], who found that translocations involving chromosome 11q15 (nucleoporin 98kD) are associated with HOX gene expression and poor prognosis. miR-181b alternatively down regulates Hox genes.…”