Acute myeloid leukaemia with NUP98 rearrangement

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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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

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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
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

Gene Mutations (SNV/INDEL)

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FLT3-ITD and WT1 mutation are recurring events in NUP98::NSD1 and was also observed in some NUP98::HOXA9 AML patients.(R1). Loss of RB1 at 13q14 is particularly associated with NUP98::KDM5A

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

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

Rearrangements involving NUP98 are often cryptic on conventional karyotype, owing to terminal location of NUP98 on chromosome 11p15.4. Most patients have a normal karyotype. Diagnosis is established using the following tests:

• FISH using NUP98 break-apart probes
• RT-PCR for fusion proteins like NUP98::NSD1
• RNA sequencing
• Optical Genome Mapping (OGM)

Karyotype image of NUP98 rearranged acute myeloid leukemia. Due to the cryptic nature of NUP98 rearrangement, karyotype is usually normal.

Optical genome mapping. Figure A showing circus plot with t(5;11). Figure B showing exact breakpoints of the translocation leading to NUP98::NSD1 fusion. Figure C showing WT1 deletion which is a common secondary event in NUP98 rearranged AML.

Familial Forms

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Links

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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.