NUP98 Fusion Proteins Are Recurrent Aberrancies in Childhood Acute Myeloid Leukemia: A Report from the AIEOP AML-2001-02 Study Group

Nucleoporin 98 (NUP98) is part of a family of proteins that are involved in the nuclear pore complex known to control trafficking of many molecules between nucleus and cytoplasm. However, NUP98 has been discovered to play a critical role in gene regulation, being involved in several chromosomal translocations in hematopoietic disorders. Up to thirty different NUP98 partner genes have been identified among patients with myelodysplastic syndrome and acute myeloid leukemia (AML). The chimeric NUP98 protein has the N-terminal of NUP98 and the C-terminal of its partner gene. Partners, if belonging to the homeobox genes conserved the DNA-binding domain, if not, they maintained chromatin interaction domains, mediating in any case a transcriptional regulatory function of the chimera, as recently described for NUP98-NSD1 and NUP98-JARID1A fusions. Here, we report the results of a study aimed at identifying the more frequent NUP98 fusion proteins present at diagnosis in children with AML treated in Italy with the AIEOP protocols.

We performed a molecular screening of 10 partner genes of NUP98, namely, NSD1, HOXC11, PHF23, HOXA9, JARID1A, HOXD13, LEDGF, DDX10, ADD3 and HHEX in 191 patients affected by de novo AML enrolled in the AIEOP LAM 2002/01 protocol, and previously found to be negative for known recurrent genetic abnormalities involving MLL, CBFB, and FLT3 genes. We found 32 positive patients (17%) harboring one of the NUP98 chimeric fusion studied, this abnormality allowing to identify a new AML subgroup. By considering the whole number of children treated with the Italian pediatric AML 2002/01 protocol, 32 out of 482 enrolled patients carried a NUP98 rearrangement, the final frequency of NUP98 aberrancies at diagnosis being 6.6 %. In detail, 12 patients were found positive for t(5;11)(q35;p15.5)NUP98-NSD1 (6 out of 12 were also FLT3ITD mutated), 5 for t(11;12)(p15;q13)NUP98-HOXC11, 3 for t(10;11) NUP98-HHEX, 3 for t(11;17)(p15.5;p13)NUP98-PHF23, 3 for t(5;11)(q35;p15.5)NUP98-JARID1A, 2 for t(10;11)NUP98-ADD3, 2 for t(7;11)(p15;p15)NUP98-HOXA9, one patient harbored t(2;11)(q31;p15)NUP98-HOXD13, one t(9;11)(p22;p15.5)NUP98-LEDGF. We then considered the NUP98 rearrangements for their clinical impact and found that the 8-year event-free survival (EFS) was significantly worse in patients with a NUP98 rearrangement (34.3%, SE 8.3) than the remaining patients negative for known recurrent genetic abnormalities (n=159, EFS = 52.3%, SE 4.3; p = 0.007). This observation was confirmed when we considered patients with NUP98 rearrangements excluding those with the FLT3ITD mutation (n=26, EFS = 34.6%).

In conclusion, we found that NUP98 is recurrently found to be involved in somatic translocations leading to childhood AML . NUP98 rearrangements identify a new subgroup of pediatric AML with a similar, dismal prognosis, deserving further consideration in novel biological studies aimed at targeting NUP98 to improve outcome.