Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene

Abstract

Chromosome rearrangements are found in many acute leukemias. As a result, genes at the breakpoints can be disrupted, forming fusion genes. One of the genes involved in several chromosome aberrations in hematological malignancies is NUP98 (11p15). As NUP98 is close to the 11p telomere, small translocations might easily be missed. Using a NUP98-specific split-signal fluorescence in situ hybridization (FISH) probe combination, we analyzed 84 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia, or myelodysplastic syndrome with either normal karyotypes or 11p abnormalities to investigate whether there are unidentified 11p15 rearrangements. Neither NUP98 translocations nor deletions were identified in cases with normal karyotypes, indicating these aberrations may be very rare in this group. However, NUP98 deletions were observed in four cases with unbalanced 11p aberrations, indicating that the breakpoint is centromeric of NUP98. Rearrangements of NUP98 were identified in two patients, both showing 11p abnormalities in the diagnostic karyotype: a t(4;11)(q1?3;p15) with expression of the NUP98-RAP1GDS1 fusion product detected in a 60-year-old woman with AML-M0, and an add(11)(p15) with a der(21)t(11;21)(p15;p13) observed cytogenetically in a 1-year-old boy with AML-M7. JARID1A was identified as the fusion partner of NUP98 using 3' RACE, RT-PCR, and FISH. JARID1A, at 12p13, codes for retinoblastoma binding protein 2, a protein implicated in transcriptional regulation. This is the first report of JARID1A as a partner gene in leukemia.

NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern

“…One pediatric case carried the NUP98/JARID1A fusion that we described previously. 27 Another pediatric case had a t(11;20)(p15; q1?2), and FISH analysis and RT-PCR confirmed the in-frame NUP98/TOP1 and reciprocal TOP1/NUP98 fusion (supplemental Figure 2). One adult case had an inv(11)(p15q22), and RT-PCR showed presence of the in-frame NUP98/DDX10 (supplemental Figure 2).…”

A new fusion gene NUP98-IQCG identified in an acute T-lymphoid/myeloid leukemia with a t(3;11)(q29q13;p15)del(3)(q29) translocation

“…Since the first description of translocation involving NUP98 at 11p15 in 1996, at least 21 different genes have been reported to fuse with NUP98 in various hematologic malignancies (Gu et al, 2003;Slape and Aplan, 2004;Gervais et al, 2005;Nebral et al, 2005;Tosi et al, 2005;van Zutven et al, 2006;Panagopoulos et al, 2007;Reader et al, 2007). NUP98 is a component of the nuclear pore complexes (NPCs) responsible for RNA and protein transport (Radu et al, 1995).…”

The histone demethylase JARID1A is associated with susceptibility to ankylosing spondylitis

“…tion may also be functionally linked through the binding of HP1, a chromodomain-containing protein that recruits DNA methyltransferases to methylate adjacent CpG islands, with consequent downregulation of gene expression. 16 The association with JARID1A reported here may be the first genetic association of a complex disease, other than cancer, 17 with a variant in a gene critical to epigenetic regulation. It is already known that small molecules, which inhibit DNA methylation (by a variety of mechanisms) can be used to treat myelodysplastic syndrome (5-azacytidine), cardiac arrhythmias (procainamide) and blood pressure (hydralazine).…”