Acute myeloid leukaemia with NUP98 rearrangement

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Eric McGinnis, MD

Fatma Albulushi, MD

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s)	Acute myeloid leukaemia with NUP98 rearrangement

Related Terminology

Acceptable	N/A
Not Recommended	N/A

Gene Rearrangements

Acute myeloid leukemia (AML) with NUP98 rearrangement is characterized by chromosomal translocations involving NUP98 (nucleoporin 98 and 96 precursor) on chromosome 11p15.4 and various partner genes - more than 40 of such have been reported to date. The NUP98 gene encodes protein component of the nuclear pore complex which facilitates nucleocytoplasmic transport of RNA and has roles in transcriptional and cell cycle regulation. NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner. Fusion partners commonly include transcription factors (such as HOX elements, most often HOXA9) or epigenetic regulators (most commonly involving NSD1 or KDM5A), however a range of partners belonging to neither of these categories has been identified, many of which contain coiled-coil domains thought to facilitate oligomerization.

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
NUP98	NUP98::NSD1	Fusion of N-terminal NUP98 (with fusion junction most often involving exons 12-13) to C-terminal NSD1; fusion proteins result in epigenetic modification and dysregulation of HOXA/HOXB family genes, among others, through functional domains in both fusion partners.	t(5;11)(q35;p15) Usually cryptic	Rare (AML)	Defining genetic abnormality in AML	Yes (WHO/ICC)	Rare though most common recurrent NUP98 rearrangement in children and young adults.
NUP98	NUP98::KDM5A	Fusion of N-terminal NUP98 (fusion junction most often involving exons 13-14) to C-terminal KDM5A; fusion proteins result in epigenetic modification and dysregulation of HOXA/HOXB family genes, among others, through functional domains in both fusion partners.	t(11;12)(p15;p13) Usually cryptic	Rare (AML)	Defining genetic abnormality in AML	Yes (WHO/ICC)	Commonly associated with erythroid and megakaryocytic phenotypes in pediatric AML (acute erythroid leukemia and acute megakaryocytic leukemia).
NUP98	NUP98::HOXA9	Fusion of N-terminal NUP98 (fusion junction most often involving exons 13-14) to C-terminal HOXA9; fusion proteins result in epigenetic modification and dysregulation of HOXA/HOXB family genes, among others, through functional domains in both fusion partners.	t(7;11)(p15;p15)	Rare (AML)	Defining genetic abnormality in AML	Yes (WHO/ICC)

Individual Region Genomic Gain/Loss/LOH

Chr#	Gain/Loss/Amp/LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
8	Gain	Trisomy 8	Unknown	NA	No
13	Loss	13q14.2q14.3	RB1	NA	No	Highly enriched in NUP98::KDM5A

Characteristic Chromosomal or Other Global Mutational Patterns

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
N/A

Gene Mutations (SNV/INDEL)

Gene	Genetic Alteration	Tumor Suppressor Gene (TSG)/Oncogene/Other	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
FLT3	Internal tandem duplication	Oncogene	Recurrent-Common (frequency varies with fusion partner)	P,T	Yes (ELN 2022; independent of fusion)	High frequency in AML with NUP98::NSD1; reported association with adverse prognosis specifically in context of NUP98::NSD1
WT1	Gain or loss of function	Oncogene/Tumor Suppressor Gene	Recurrent-Common (frequency varies with fusion partner)		No	High frequency in AML with NUP98::NSD1; reported association with adverse prognosis specifically in context of NUP98::NSD1
KRAS	Gain of function	Oncogene	Recurrent		No
NRAS	Gain of function	Oncogene	Recurrent		No

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

NUP98 fusion proteins are understood to generally mediate leukemogenesis through the functions of protein domains present in wild-type NUP98 and the relevant fusion partner (often harbouring transcriptional or chromatin-modifying properties); in vitro experiments have demonstrated chromatin remodeling related to fusion oncoprotein expression (and associated with coordination of numerous interacting proteins, including transcriptional cofactors (e.g. EP300, CREBBP, MEIS1) and histone-modifying complexes) resulting in dysregulation of expression of members of the HOXA and HOXB gene families, among other loci (e.g. MEIS1).

Genes and Main Pathways Involved

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
Various NUP98 fusions	HOX-family pathways	Disruption of critical hematopoietic regulator; dysregulation of differentiation, proliferation, apoptosis, and cell survival.

Genetic Diagnostic Testing Methods

Several common rearrangements involving NUP98 (with NSD1 and KDM5A) are generally cryptic in conventional karyotyping owing to the terminal locations of loci involved, while other rearrangements involving NUP98 may be visible in banded chromosomes. The following techniques may be used to facilitate detection of cryptic rearrangements:

• FISH (e.g. locus-specific NUP98 break-apart probe)
• RT-PCR assays for detection of specific fusions
• RNA sequencing
• Optical genome mapping
  

Cytogenetically cryptic NUP98::NSD1 rearrangement detected by optical genome mapping. Panel A: Circos plot depicting t(5;11)(q35.3;p15.4) with inset of chromosomes 5 and 11 showing no visible abnormalities in banded chromosomes. Panel B: NUP98::NSD1 fusion variant call. Panel C: Concurrent deletion of WT1; abnormalities of WT1 are highly recurrent in AML with NUP98::NSD1.

Familial Forms

Not applicable.

Additional Information

NUP98 fusions are not specific for de novo acute myeloid leukemia, also occurring in T-lymphoblastic leukemia and blast phase chronic myeloid leukemia with overlap in the profile of NUP98 fusion partners (though HOX fusions appear, in reports to date, to be specific to myeloid neoplasms).

Links

Not applicable.

References

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Notes

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Prior Author(s):

*Citation of this Page: “Acute myeloid leukaemia with NUP98 rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/30/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NUP98_rearrangement.