Screening for NUP98 rearrangements in hematopoietic malignancies by fluorescence in situ hybridization

Background and Objectives. The aim of this study was to determine the incidence of rearrangements of NUP98 (the gene coding for nucleoporin 98kDa protein) in childhood acute myeloid leukemia (AML) and selected patients with 11p13-15 rearrangements. This aim was achieved using a fluorescence in situ hybridization (FISH) assay that allows the detection of NUP98 aberrations independently of the partner gene involved. Design and Methods. Screening of 59 consecutive patients enrolled in the Austrian AML-BFM93 clinical trial was performed by dual-color FISH. In addition, 14 selected cases with various hematologic malignancies and 11p13-15 aberrations were analyzed. NUP98-positive cases were further investigated by fusion gene-specific FISH and reverse transcription polymerase chain reaction assays. Results. Among the 59 AML patients, one NUP98-NSD1 positive case (1.7%) was detected. Among the 14 selected patients, five new NUP98 positive cases were determined. Two cases showed an inv(11)(p15q22)/NUP98-DDX10 fusion, one each displayed a t(5;11)(q35;p15)/NUP98-NSD1 and a t(11;20)(p15;q12)/NUP98-TOP/ fusion, and one case with a putative new fusion partner gene at 3p24 was identified. Interpretation and Conclusions. The observed frequency of 1.7% confirmed the low incidence of NUP98 rearrangements in childhood AML. The low occurrence of NUP98 rearrangements in selected samples with 11p13-15 alterations suggests the existence of variable chromosomal breakpoints and affected genes in this region. The identification of a new NUP98 fusion partner region confirms the evident promiscuity of NUP98. Thus, analysis of NUP98 aberrations by FISH seems to be the method of choice for determining the presence of these genetic lesions in unselected patients, and to confirm the involvement of NUP98 in cases with 11p15 aberrations.