NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis

Abstract

Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.

Somatic mutations in murine models of leukemia and lymphoma: Disease specificity and clinical relevance

“…FLT3 mutations are common in unselected AML patients, and were recently found to occur in 36‐63% of NUP98 ‐rearranged AML . We found Flt3 mutations in the murine AML samples, but not the murine PTCLs.…”

“…It seems feasible that the disease latency reflects the mutational processes required to generate cancer‐ the stronger the driver mutation is, the fewer additional mutations are needed and the shorter the disease latency will be. Of note, NUP98 fusions are likely to be early, initiating events in human AML, similar to murine models in which transgenes engineered into the murine germline are initiating events.…”

“…15,16 Although NUP98 fusions have been considered rare events in patients with AML, recent studies show that NUP98 fusions are present in approximately 5% of all pediatric AML patients, and as many as 15% of "normal karyotype" pediatric AML patients. [17][18][19][20] A third murine model of AML that we studied was generated by expression of a CALM-AF10 transgene. 21 CALM-AF10 fusions are associated with AML and immature T-ALL in humans; the AML in both human patients and engineered murine models are characterized by clonal rearrangements of both IG and TCR genes, [22][23][24] suggesting that the cell of origin is multipotent.…”

NUP98‐BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy

“…NUP98‐BPTF was not reported among the gene fusions identified in a sampling of 197 pediatric AML interrogated by whole genome sequencing and supported by RNAseq or cytogenetic data . Nonetheless, out of 574 pediatric AML specimens interrogated by targeted approaches (e.g., cytogenetics, FISH, and selected RNAseq), 22 harbored a NUP98 rearrangement (3.8%) and one of them presented a complex karyotype with a t(11;17) (p15;q23) translocation, as detected in this AMLK case, involving an undefined NUP98 partner (CK#14) . The NUP98 fusion partner could not be identified by RNAseq since RNA was not available .…”

“…NUP98 rearrangements most frequently associated with pediatric AML include NUP98‐NSD1 (nuclear receptor binding SET domain protein 1) and NUP98‐KDM5A, both part of group II. Overall, ∼4% of pediatric AML cases harbor NUP98 rearrangements and they are generally associated with poor patient outcomes, with high rate of induction chemotherapy failure, and low cure rates . Overexpression of NUP98‐KDM5A in BM cells is sufficient to generate short latency AML in mice, and the PHD domain plays a critical role in leukemic transformation by this fusion.…”