NUP98 – acute myeloid leukemia

Nucleoporin gene NUP98 is recurrently rearranged in acute myeloid leukemia (AML) through translocations involving its FG­repeat–containing N-terminal domain. The first description of a NUP98 fusion partner in AML identified NUP98-HOXC11 resulting from t(11;12)(p15;q13), establishing 11p15 as a hotspot for leukemogenic events (PMID:12183408) and revealing that NUP98 fusions capture homeobox domains from diverse partners.

Subsequent multi-patient studies demonstrated NUP98 fusions in 24 pediatric acute erythroid leukemia cases (31.8% prevalence) enriched for NUP98 chimeras and identified a cryptic t(5;11)(q35;p15.5) generating NUP98-NSD1 in 2 of 69 cytogenetically normal AMLs (PMID:33284945, PMID:11895789). Collectively, over 25 fusion partners have been reported in AML, including HOXA, HOXC, NSD1, NSD3, DDX10, ASH1L, and others.

NUP98-NSD1 is one of the most prevalent fusions in cytogenetically normal pediatric AML and frequently co-occurs with FLT3-ITD. These somatic events define a distinct molecular subgroup with poor prognosis. Fusions uniformly retain the NUP98 FG repeats fused in-frame to partner homeobox or chromatin-modifying domains, confirming a shared gain-of-function mechanism.

Functional modeling in mice shows that expression of NUP98-NSD1 confers aberrant self-renewal to hematopoietic progenitors, and co-expression with FLT3-ITD dramatically accelerates AML onset with short latency and penetrance, whereas either lesion alone is insufficient for leukemogenesis (PMID:24951466). This synergy mirrors the frequent co-mutational spectrum observed in patients.

Mechanistic studies reveal that NUP98 fusions form nuclear FG-repeat condensates recruiting chromatin remodelers such as SMARCA5, which are essential for transformation, and aberrantly bind CRM1 to inhibit nuclear export of key transcription factors, leading to nuclear entrapment of NFAT and NFκB and dysregulated transcription (PMID:35073946, PMID:20233715).

Integrating genetic and experimental data establishes a definitive role for NUP98 fusions as drivers of AML. Detection of specific NUP98 fusion transcripts by FISH or sequencing is critical for diagnosis, risk stratification, and guiding FLT3-targeted or export-inhibition therapies. Key Take-home: NUP98 fusions are actionable biomarkers in AML informing prognosis and therapeutic strategies.

References

• Blood advances • 2020 • Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group. PMID:33284945
• Blood • 2002 • A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay. PMID:11895789
• Cancer research • 2002 • Novel NUP98-HOXC11 fusion gene resulted from a chromosomal break within exon 1 of HOXC11 in acute myeloid leukemia with t(11;12)(p15;q13). PMID:12183408
• Haematologica • 2014 • Potent co-operation between the NUP98-NSD1 fusion and the FLT3-ITD mutation in acute myeloid leukemia induction. PMID:24951466
• The Journal of biological chemistry • 2010 • Inhibition of CRM1-mediated nuclear export of transcription factors by leukemogenic NUP98 fusion proteins. PMID:20233715
• Journal of experimental & clinical cancer research : CR • 2022 • SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation. PMID:35073946

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