The Concurrent Mutations in Hematological Malignancies with NUP98-Fusion Genes Are Associated with Clinical Prognosis

Abstract 1480

Genetic alterations such as translocations, gene mutations and deletions play an important role in myeloid leukemogenesis resulting from the deregulated proliferation and differential loss of normal hematopoietic stem or progenitor cells. Recently, definitive combination of gene alterations in myeloid malignancies was reported although many gene alterations were found in AML or MDS. It is considered that the combination of mutations determine both clinical characteristics and leukemogenesis. In the hematological malignancies with chromosomal translocations involving 11p15, the NUP98 gene has been reported to be fused to a number of miscellaneous partner genes. Most patients with NUP98-HOX fusion genes are diagnosed as myeloid malignancies. The prognosis of the patients with NUP98 -fusion leukemia is considered to be dismal. However, the relationship between clinical characteristics and the concurrent mutations in hematological malignancies harboring NUP98 -fusion genes remain unclear. Herein, we examined the concomitant somatic mutations in 20 patients with hematological malignancies harboring NUP98- fusion to determine if their clinical features and concurrent mutations are associated. Mutations were searched on FLT3, KIT, RAS, AML1, MLL, NPM1, CEBPA, WT1, IDH1, IDH2, and MPL genes. The 20 patients include 8 females and 12 males ranging from 3 to 69 years old. There were 13 patients with AML (7 FAB-M2s, 5 FAB-M4s, and 1 FAB-M1), 3 cases with MDS (2 RAs and 1 RAEB), and 3 subjects with MPD (CMML, Ph-negative CML, and JMML, respectively). The remaining one patient was diagnosed as T-cell non-Hodgkin lymphoma. These patients include 10 cases with NUP98-HOXA9, 2 with NUP98-HOXA13, NUP98-HOXA11, NUP98-HOXD13, and NUP98-DDX10, one each with NUP98-HOXC11, NUP98-HOXD11, and NUP98-NSD3. Eighteen patients except for 2 cases with NUP98-DDX10 were de novo leukemia. In AML patients, most cases with NUP98-HOXA fusions were found in FAB-M2 phenotype, while those with NUP98-HOXD fusions were FAB-M4 phenotype. FLT3 -ITD was found in 9 of 20 patients (45 %). Mutations on KIT were identified in 4 patients (20 %), NRAS mutations were detected in 4 patients (20 %), KRAS mutations were present in 2 patients (11 %), and WT1 aberrations existed in 8 patients (40 %). Mutations on IDH1 and IDH2 were identified in 2 patients (10%), and in 1 patient (5%), respectively. In contrast, mutations in the tyrosine kinase domain on FLT3 gene, AML1, CEBPA, NPM1, MLL or MPL1 genes were not identified. Fifteen (75%) of the 20 patients had either FLT3 -ITD or RAS mutations, but they were mutually exclusive. Six of 8 patients with WT1 aberrations had FLT3 -ITD, and the other 2 patients had RAS mutations. All patients with KIT mutations, or WT1 alterations and 2 of 3 cases with IDH1 or IDH2 mutations had other additional mutations. FLT3 -ITD were identified at higher frequency in male than female (p=0.01) and associated with leukocytosis. Among 9 patients with FLT3 -ITD, 7 of them died (78%). Similarly, 2 cases out of 4 cases with NRAS mutations died. In contrast, all patients with KRAS, IDH1, or IDH2 mutations were alive, suggesting that FLT3 -ITD or NRAS mutations confer poorer prognosis of the patients with NUP98 -fusion compared to those with KRAS, IDH1, or IDH2 mutations. However, all 3 patients with NUP98-HOXD fusions were alive though they had additional mutations of FLT3 or RAS mutations.These results suggest that prognosis of leukemia with NUP98 -fusion may depend on the concomitant gene alterations, in addition to fusion partner genes of NUP98. Moreover, existence of mutations on the preferential genes strongly suggests that leukemogenesis induced by NUP98 -fusions may depend on the mutations on selective genes. While FLT3 or NRAS mutations that were identified at high frequency in the patients with NUP98 -fusion genes showed poorer prognosis of the patients with NUP98 -fusion leukemia, concomitant existence of KIT, WT1, IDH1, or IDH2 mutations strongly suggest that they may also play pathological roles in the hematological malignancies with NUP98 -fusion.