Loss of Heterozygosity (LOH) of the NUP98 Gene Is an Adverse Prognostic Factor in Acute Myeloid Leukemia (AML).

The NUP98 gene on chromosome 11p15 encodes a 98kDa protein component of the nuclear pore complex that is involved in the nucleocytoplasmic transport of proteins and RNAs. Chromosomal translocations creating NUP98 fusion genes have been described in various hematologic malignancies including AML and myelodysplastic syndromes (MDS). The molecular mechanisms involving NUP98 gene locus and its function in leukemogenesis remain unknown, however, frequent allelic loss at the 11p locus has been reported in solid tumors and AML. We have evaluated NUP98 gene disruption by LOH in AML subtypes and correlated LOH with clinical outcomes including disease relapse and survival rates. A total of 101 patients with AML and 49 with MDS treated between 2002–2006 were evaluated for LOH at five markers in and around the NUP98 gene. We found a high frequency of 11p15 LOH of the NUP98 region in patients with overt AML (32/101) and a lower frequency in preleukemic MDS patients (4/49). The median follow-up for survivors was 26 months (range 15–43). Patients with NUP98 LOH had a significantly decreased overall survival as compared to patients without NUP98 LOH (median survival 4 and 13 months, respectively, p=0.007). In the subset of patients with no evidence of disease after treatment (n=57), the presence of NUP98 LOH was significantly associated with a decreased disease free interval (5 months vs. 24 months, p <0.0001). The NUP98 disruption was not associated with age, gender, cytogenetic findings, FAB subtype, FLT3-ITD status, prior history of MDS, WBC or platelet counts as confirmed by multivariate statistical model. We did not observe the silencing of the NUP98 gene by methylation of its promoter compared to the p57 gene, located on the same chromosome. In addition to LOH, we screened for chromosomal translocations involving the NUP98 region. In one AML patient we found both NUP98-HOXA9 translocation and LOH. By using the NUP98 antibody that detects both wild type and fusion protein, we found a significantly impaired localization of NUP98 protein and the presence of NUP98 co-localization aggregates within both the nucleus and cytoplasm of one patient, which indicated both NUP98-HOXA9 translocation and LOH. In summary, NUP98 LOH is associated with a worse clinical outcome for AML patients. The presence of NUP98 LOH supports the hypothesis that NUP98 allelic loss may be an important event in de novo leukemogenesis, when leukemia develops after MDS. NUP98 translocations associated with NUP98 fusions contribute to leukemogenesis, particularly in association with NUP98 LOH.