Nucleoporins (NUP) are a family of proteins that form the building blocks of the nuclear pore complex. Translocations involving NUP family members have been reported in acute myeloid leukemia (AML) as predictors of poor outcome. Using whole transcript sequencing we identified NUP98/NSD1 translocations in 2 AML patients; both were cytogenetically normal (CN) and harbored FLT3/ITD. We therefore performed a comprehensive study on the prevalence of NUP98/NSD1 in children and adult AML patients to define the prognostic significance of this translocation and its contribution to clinical outcome.

NUP98/NSD1 was evaluated using RT-PCR and the fusion transcripts were verified by Sanger sequencing. Presence of NUP98/NSD1 transcript was initially assessed on all available diagnostic specimens from patients treated in COG AAML03P1. As this transcript was detected only in patients with CN-AML or FLT3/ITD, the remaining evaluations on CCG2961, COG AAML0531 and SWOG0106 were limited to this patient population. Presence of NUP98/NSD1 was correlated with disease characteristics and clinical outcome.

We initially assessed the impact of the NUP98/NSD1 in children with FLT3/ITD. Of the 2486 patients treated in 3 pediatric trials (age >1 month to < 30 years), 373 had FLT3/ITD (15%), of whom 16% also harbored NUP98-NSD1. Demographics and disease characteristics of FLT3/ITD patients were compared between those with and without NUP98/NSD1. NUP98/NSD1 was significantly associated with younger age, intermediate risk cytogenetics, higher marrow blast %, white blood and platelet count. Mutations in NPM1 and CEBPA were not detected in those with dual FLT3/ITD and NUP98/NSD1 alterations, whereas WT1 was enriched in these patients as compared to those with FLT3/ITD without NUP98/NSD1 (40.6% vs 17.3%, p=0.004). Patients with FLT3/ITD who also harbored NUP98/NSD1 had significantly worse complete remission (CR) rates (28% vs 69%, p<0.001), overall survival (3-year OS 32% vs 55%, p=0.004) and event-free survival (3-year EFS 16% vs 38%, p<0.001) than those with FLT3/ITD without NUP98/NSD1. Minimal residual disease (MRD) was also significantly higher in patients with dual FLT3/ITD and NUP98/NSD1 alterations as compared to those with FLT3/ITD without NUP98/NSD1 (76% vs 36.5%, p<0.0029). Within the FLT3/ITD cohort, in multivariate analysis including other known prognostic factors (such as cytogenetics, WBC, bone marrow blast %, NPM1, CEBPA and WT1), NUP98/NSD1 remained an independent predictor of poor CR rate. In CN-AML pediatric patients (N=267), the prevalence NUP98/NSD1 was 8%, of which 73% of were also FLT3/ITD. The CR rate for CN-AML harboring NUP98/NSD1 was significantly lower than in those without it (50% vs. 78%, p=0.008) and patients with both NUP98/NSD1 and FLT3/ITD had CR rate of 38% compared to that of 83% in patients with NUP98/NSD1 without FLT3/ITD.

We also evaluated NUP98/NSD1 in patients treated on SWOG 0106. Of the 595 patients enrolled (age >18 to <60 years), 133 with either CN-AML or FLT3/ITD had available diagnostic specimens for analysis. Within the FLT3/ITD cohort, 8.5% (5 out of 59) patients also harbored NUP98/NSD1. Four of these 5 patients failed to achieve CR; the only patient with dual FLT3/ITD and NUP98/NSD1 alteration who achieved CR, died within a year of relapsed AML. There was only 1 patient with CN-AML with NUP98/NSD1 who did not harbor FLT3/ITD. This was the only patient who achieved and remained alive at 4.5 years of follow-up. The CR rate among FLT3/ITD patients without NUP98/NSD1 was 69%.

In this large cooperative study we demonstrated that NUP98/NSD1 is commonly seen in children and young adults with AML with high association with CN-AML and very high overlap with FLT3/ITD. Although the CR rate is not affected in those with FLT3/ITD, we demonstrated that those with dual FLT3/ITD and NUP98/NSD1 alterations have extremely low CR rate and high post-induction MRD than FLT3/ITD patients without NUP98/NSD1. In contrast, NUP98/NSD1 patients without FLT3/ITD have a more favorable CR rate and survival. Within FLT3/ITD patients, the presence of NUP98/NSD1 can be used to identify those at very high risk for induction failure. The high simultaneous frequency of NUP98/NSD1 and WT1 in FLT3/ITD AML suggests a cooperative mechanism among these genetic lesions into leukemogenesis. Targeted therapy strategies should be developed for this subgroup of patients with highly resistant disease.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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