Acute myeloid leukaemia with NUP98 rearrangement
Haematolymphoid Tumours (WHO Classification, 5th ed.)
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Somatic Disease Template with Instructions
(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author Instructions and FAQs as well as contact your Associate Editor or [Support].)
Primary Author(s)*
Eric McGinnis, MD
Fatma Albulushi, MD
WHO Classification of Disease
(Instructions: This table’s content from the WHO book will be autocompleted.)
| 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 |
WHO Essential and Desirable Genetic Diagnostic Criteria.
(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)
| WHO Essential Criteria (Genetics)* | Detection of NUP98 rearrangement |
| WHO Desirable Criteria (Genetics)* | Identification of the NUP98 fusion partner |
| Other Classification | Myeloid blast count may <20% |
*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
Related Terminology
(Instructions: The table will have the related terminology from the WHO autocompleted)
| Acceptable | NA |
| Not Recommended | NA |
Gene Rearrangements
Acute myeloid leukaemia (AML) with NUP98 rearrangement is characterized by chromosomal translocations involving NUP98 (nucleoporin 98 kDa) on chromosome 11p15.4 and various partner genes. (Reference WHO book). There are over 40 fusion partners which have been reported to date. NUP98 fusions can be categorized into three broad parts. The first category includes NUP98 fusions with transcription factors as partners, which can change the expression of target genes through DNA binding domains. The second category is NUP98 fusions with epigenetic modifiers that modify chromatin to change target gene expression. The third category of NUP98 fusions has neither the DNA binding nor chromatin remodeling domain. [1](see figure)
The NUP98 gene (chromosome 11p15) encodes a nucleoporin protein, which is part of the nuclear pore complex which regulates nucleocytoplasmic transport of protein and RNA. NUP98 fusion proteins involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner. These fusion partners consist of homeodomain proteins, which are transcription factors, and non-homeodomain proteins, which are thought to play a role in transcriptional or epigenetic regulation. [1][2]
| 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
|
NUP98-NSD1 prevents EZH2-mediated repression of Hox-A locus genes by colocalizing H3K36 methylation and histone acetylation at regulatory DNA elements hence preventing myeloid progenitor immortalization | t(5;11)(q35;p15)
Usually cryptic |
Rare (AML) | Defining genetic abnormality in AML | Yes (WHO) | Rare but recurrent alteration seen mainly in children and young adults with AML. Poor overall survival, disease free survival, induction failure and chemotherapy resistance [2] |
| NUP98 | NUP98::KDM5A | KDM5A is an epigenetic-modifying partners of NUP98 which dysregulate Hox genes expression through recognition of H3K4me3/2 marks by the plant homeodomain (PHD) finger domain | t(11;12)(p15;p13)
Usually cryptic |
Rare (AML) | Defining genetic abnormality in AML | Yes (WHO) | Commonly associated with erythroid and megakaryocytic phenotypes in pediatric AML (acute erythroid leukemia and acute megakaryocytic leukemia). [2]
Unfavorable outcomes |
| NUP98 | NUP98::HOXA9
|
NUP98 fusions bind near the HOX genes loci and activate their expression through chromatin remodeling. The overexpression of distal HoxA cluster genes promote self-renewal and drive leukogenesis | t(7;11)(p15, p15) | Rare (AML) | Defining genetic abnormality in AML |
Individual Region Genomic Gain/Loss/LOH
No characteristic chromosomal gain or loss. However, trisomy 8 and chromosome 13 abnormalities may be observed.
Several reports indicated that del(13q) is a frequent event in NUP98::KDM5A AML patients, indicating co-occurrence of NUP98-KDMA fusion with RB1 deletion. (WHO book)
| Chromosome Number | 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 | Deletion of 13q | RB1 gene | NA | Particularly associated with NUP98::KDM5A |
Characteristic Chromosomal or Other Global Mutational Patterns
Put your text here (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete table.)
| 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 19q |
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)
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-ITD | ||||||
| WT1 | ||||||
| RB1 |
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
Put your text here
Genes and Main Pathways Involved
Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete table.)
| 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
· FISH using NUP98 break-apart probes
· RT-PCR for fusion proteins like NUP98::NSD1
· RNA sequencing
· Optical Genome Mapping (OGM)
Familial Forms
Put your text here (Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.)
Additional Information
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.
Links
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References
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
Prior Author(s):
- ↑ 1.0 1.1 Mohanty, Sagarajit (2023-09). "NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications". Onco. 3 (3): 147–164. doi:10.3390/onco3030011. ISSN 2673-7523. Check date values in:
|date=(help) - ↑ 2.0 2.1 2.2 Bertrums, Eline J. M.; et al. (2023-02-23). "Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia". Haematologica. 108 (8): 2044–2058. doi:10.3324/haematol.2022.281653. ISSN 1592-8721.