High Frequencies of Simultaneous FLT3-ITD, WT1, and KIT mutations in NUP98-Related Hematologic Malignancies.

Abstract 2620

Poster Board II-596

Leukemia is heterogeneous in clinical features as well as in molecular pathogenesis. Cooperating alterations of several genes including oncogenes or tumor suppressor genes lead to development of Leukemia. In hematologic malignancies with chromosomal 11p15 translocations, the NUP98 gene has been reported to be fused to many partner genes, such as HOXA9/A11/A13, HOXC11/C13, HOXD11/D13, NSD1/3, DDX10, or PMX1. Most patients with NUP98-HOX fusion genes were myeloid malignancies. The outcome of the patients with NUP98-fusion leukemia was considered to be dismal. However, additional gene mutations in hematologic malignancies with NUP98-fusion genes and the clinical significance of those mutations remain unknown. We examined somatic mutations in 19 patients with hematologic malignancies having NUP98-fusion fusions and correlation between clinical features and somatic mutations detected. The age of 19 patients was from 3 to 69. The male-female ratio was 12 to 7. Eightteen of 19 patients with NUP98-related hematologic malignancies were diagnosed as having myeloid malignancies, and the other one as T-cell non-Hodgkin lymphoma. Patients with myeloid malignancies consist of 12 patients with AML (7 FAB-M2s, 4 FAB-M4s, and 1 FAB-M1), 3 patients with MDS (2 RAs and 1 RAEB), and 3 patients with MPD (CMML, Ph-negative CML, and JMML, respectively). These patients include 10 cases with NUP98-HOXA9, 2 with NUP98-HOXA13, NUP98-HOXA11, and NUP98-DDX10, one each with NUP98-HOXC11, NUP98-HOXD11, NUP98-HOXD13, and NUP98-NSD3. Only 2 of 11 patients with t(7;11)(p15;p15) had double-fusion transcripts, one had NUP98-HOXA9 and NUP98-HOXA11, the other had NUP98-HOXA9 and NUP98-HOXA13. Seventeen 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. The WBC at diagnosis tended to be higher. Additional chromosomal abnormalities besides 11p15 translocation were rare. Notably, FLT3-ITD was found in 9 (47.3 %) of 19 patients, KIT mutations in 4 patients (21.0 %), NRAS mutations in 3 patients (15.8 %), KRAS mutations in 2 patients (10.6 %), and WT1 aberrations in 8 patients (42.1 %). No mutations were found in FLT3-tyrosine kinase domain, AML1, CEBPA, NPM1 or MLL genes. The mutations in KIT were all missense mutations including Val399Ile, Met541Leu, and Asp816Val, all mutations of NRAS and KRAS were Gly13Asp, and the aberrations in WT1 comprised frameshift insertion of exon 7 in 4 patients, misssense mutation of exon 9 in 1, deletion of exon 5, and deletion of whole cording region in 2. Interestingly, 6 of 8 patients with WT1 aberrations had FLT3-ITD, and 4 patients with both FLT3-ITD and WT1 aberrations had KIT mutation. Patients with FLT3-ITD significantly occurred more in male than female (p=0.01) and tended to have leukocytosis. All 4 patients with KIT mutations had both FLT3-ITD and WT1 aberrations (p=0.04, and p=0.03, respectively). Patients with RAS mutations were significantly younger than those without the mutations (19 years vs 44 years on average) (p=0.04). All 5 patients with RAS mutations had neither FLT3-ITD nor WT1 aberrations. Five of 6 patients having both FLT3-ITD and WT1 aberrations died, including all 4 cases harboring KIT mutations. Two of 3 patients with NRAS mutations also died, while all 2 patients with KRAS mutation were alive. These results suggest that high frequency of mutations of the genes involved in cell proliferation in hematologic malignancies with NUP98-fusion genes may accelerate leukemogenesis, and that simultaneous occurrence of FLT3-ITD, and WT1 aberrations may play an important role for clinical outcome in NUP98-related leukemia.