HAEM5:Acute myeloid leukaemia with NUP98 rearrangement: Difference between revisions

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__TOC__
==Primary Author(s)*==


Somatic Disease Template with Instructions
Eric McGinnis, MD, Vancouver General Hospital


(''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 [[Frequently Asked Questions (FAQs)|FAQs]] as well as contact your [[Leadership|Associate Editor]] or [[Mailto:CCGA@cancergenomics.org|Technical Support]].'')
Fatma Albulushi, MD, University Medical City
==WHO Classification of Disease==


'''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.'')
{| class="wikitable"
{| class="wikitable"
!Structure
!Disease
|-
|Book
|Book
|Haematolymphoid Tumours (5th ed.)
|Haematolymphoid Tumours (5th ed.)
|-
|-
|Category
|Category
|Myeloid proliferations and neoplasms
|Myeloid proliferations and neoplasms
|-
|-
|Family
|Family
|Acute myeloid leukaemia
|Acute myeloid leukaemia
|-
|-
|Type
|Type
|Acute myeloid leukaemia with defining genetic abnormalities
|Acute myeloid leukaemia with defining genetic abnormalities
|-
|-
|Subtype(s)
|Subtype(s)
|Acute myeloid leukaemia with NUP98 rearrangement
|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.'')
{| class="wikitable"
|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%
|}
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.


'''Related Terminology'''
==Related Terminology==


(''Instructions: The table will have the related terminology from the WHO autocompleted'')
{| class="wikitable"
{| class="wikitable"
|+
|Acceptable
|Acceptable
|NA
|N/A
|-
|-
|Not Recommended
|Not Recommended
|NA
|N/A
|}
|}


 
==Gene Rearrangements==
'''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.<ref name=":5">Patkar N, Meshinchi S, Westerman D, et al. Acute myeloid leukaemia with NUP98 rearrangement. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; 2024. . (WHO classification of tumours series, 5th ed.; vol. 11). <nowiki>https://publications.iarc.who.int/637</nowiki>.</ref> 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.<ref name=":2">{{Cite journal|last=Gough|first=Sheryl M.|last2=Slape|first2=Christopher I.|last3=Aplan|first3=Peter D.|date=2011-12-08|title=NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights|url=https://pubmed.ncbi.nlm.nih.gov/21948299|journal=Blood|volume=118|issue=24|pages=6247–6257|doi=10.1182/blood-2011-07-328880|issn=1528-0020|pmc=3236115|pmid=21948299}}</ref><ref name=":4">{{Cite journal|last=Michmerhuizen|first=Nicole L.|last2=Klco|first2=Jeffery M.|last3=Mullighan|first3=Charles G.|date=2020-11-12|title=Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies|url=https://pubmed.ncbi.nlm.nih.gov/32766874|journal=Blood|volume=136|issue=20|pages=2275–2289|doi=10.1182/blood.2020007093|issn=1528-0020|pmc=7702474|pmid=32766874}}</ref> NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner.<ref name=":2" /> 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.<ref name=":0">{{Cite journal|last=Mohanty|first=Sagarajit|date=2023-09|title=NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications|url=https://www.mdpi.com/2673-7523/3/3/11|journal=Onco|language=en|volume=3|issue=3|pages=147–164|doi=10.3390/onco3030011|issn=2673-7523}}</ref>
 
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. <ref name=":0">{{Cite journal|last=Mohanty|first=Sagarajit|date=2023-09|title=NUP98 Rearrangements in AML: Molecular Mechanisms and Clinical Implications|url=https://www.mdpi.com/2673-7523/3/3/11|journal=Onco|language=en|volume=3|issue=3|pages=147–164|doi=10.3390/onco3030011|issn=2673-7523}}</ref>(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. <ref name=":0" /><ref name=":1">{{Cite journal|last=Bertrums|first=Eline J. M.|last2=Smith|first2=Jenny L.|last3=Harmon|first3=Lauren|last4=Ries|first4=Rhonda E.|last5=Wang|first5=Yi-Cheng J.|last6=Alonzo|first6=Todd A.|last7=Menssen|first7=Andrew J.|last8=Chisholm|first8=Karen M.|last9=Leonti|first9=Amanda R.|date=2023-02-23|title=Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia|url=https://www.haematologica.org/article/view/haematol.2022.281653|journal=Haematologica|language=en|volume=108|issue=8|pages=2044–2058|doi=10.3324/haematol.2022.281653|issn=1592-8721}}</ref>
<br />
{| class="wikitable"
{| class="wikitable"
|'''Driver Gene'''
|'''Driver Gene'''
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|'''Typical Chromosomal Alteration(s)'''
|'''Typical Chromosomal Alteration(s)'''
|'''Prevalence -Common >20%, Recurrent  5-20% or Rare <5% (Disease)'''
|'''Prevalence -Common >20%, Recurrent  5-20% or Rare <5% (Disease)'''
|'''Diagnostic,  Prognostic, and Therapeutic Significance - D, P, T'''  
|'''Diagnostic,  Prognostic, and Therapeutic Significance - D, P, T'''
|'''Established  Clinical Significance Per Guidelines - Yes or No (Source)'''
|'''Established  Clinical Significance Per Guidelines - Yes or No (Source)'''
|'''Clinical  Relevance Details/Other Notes'''
|'''Clinical  Relevance Details/Other Notes'''
Line 86: Line 57:
|''NUP98''
|''NUP98''
|''NUP98::NSD1''
|''NUP98::NSD1''
<br />
|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.
|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)
|t(5;11)(q35;p15)


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|Rare (AML)
|Rare (AML)
|Defining genetic abnormality in AML
|Defining genetic abnormality in AML
|Yes (WHO)
|Yes (WHO/ICC)
|Rare but recurrent alteration seen mainly in children and young adults with AML. Poor overall survival, disease free survival, induction  failure and chemotherapy resistance <ref name=":1" />
|Rare though most common recurrent NUP98 rearrangement in children and young adults.<ref name=":1">{{Cite journal|last=Bertrums|first=Eline J. M.|last2=Smith|first2=Jenny L.|last3=Harmon|first3=Lauren|last4=Ries|first4=Rhonda E.|last5=Wang|first5=Yi-Cheng J.|last6=Alonzo|first6=Todd A.|last7=Menssen|first7=Andrew J.|last8=Chisholm|first8=Karen M.|last9=Leonti|first9=Amanda R.|date=2023-02-23|title=Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia|url=https://www.haematologica.org/article/view/haematol.2022.281653|journal=Haematologica|language=en|volume=108|issue=8|pages=2044–2058|doi=10.3324/haematol.2022.281653|issn=1592-8721}}</ref>
|-
|-
|''NUP98''
|''NUP98''
|''NUP98::KDM5A''
|''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
|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)
|t(11;12)(p15;p13)


Line 104: Line 74:
|Rare (AML)
|Rare (AML)
|Defining genetic abnormality in AML
|Defining genetic abnormality in AML
|Yes (WHO)
|Yes (WHO/ICC)
|''Commonly associated with erythroid and megakaryocytic phenotypes in pediatric AML (acute erythroid leukemia and acute megakaryocytic leukemia).'' <ref name=":1" />  
|Commonly associated with erythroid and megakaryocytic phenotypes in pediatric AML (acute erythroid leukemia and acute megakaryocytic leukemia). <ref name=":1" />
 
''Unfavorable outcomes''
|-
|-
|''NUP98''
|''NUP98''
|''NUP98::HOXA9''
|''NUP98::HOXA9''
<br />
|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.
|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)
|t(7;11)(p15, p15)
|Rare (AML)
|Rare (AML)
|Defining genetic abnormality in AML
|Defining genetic abnormality in AML
|
|Yes (WHO/ICC)
|
|
|}
|}


 
==Individual Region Genomic Gain/Loss/LOH==
'''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)
<br />
{| class="wikitable"
{| class="wikitable"
|'''Chromosome Number'''  
|'''Chr#'''
|'''Gain/Loss/Amp/LOH'''
|'''Gain/Loss/Amp/LOH'''
|'''Minimal Region Cytoband and/or Genomic  Coordinates [Genome Build; Size]'''
|'''Minimal Region Cytoband and/or Genomic  Coordinates [Genome Build; Size]'''
|'''Relevant Gene(s)'''
|'''Relevant Gene(s)'''
|'''Diagnostic,  Prognostic, and Therapeutic Significance - D, P, T'''  
|'''Diagnostic,  Prognostic, and Therapeutic Significance - D, P, T'''
|'''Established  Clinical Significance Per Guidelines - Yes or No (Source)'''
|'''Established  Clinical Significance Per Guidelines - Yes or No (Source)'''
|'''Clinical  Relevance Details/Other Notes'''
|'''Clinical  Relevance Details/Other Notes'''
Line 140: Line 101:
|Trisomy 8
|Trisomy 8
|Unknown
|Unknown
|NA  
|NA
|No
|No
|
|
|-
|-
|13
|13
|loss
|Loss
|Deletion of 13q
|13q14.2q14.3<ref name=":2" />
|RB1 gene
|''RB1''
|NA
|NA
|
|No
|Particularly associated with NUP98::KDM5A
|Highly enriched in ''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.'')
 
{| class="wikitable"
|'''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
==Characteristic Chromosomal or Other Global Mutational Patterns==
|EXAMPLE:  See  chromosomal rearrangements table as this pattern is due to an unbalanced  derivative translocation associated with oligodendroglioma (add reference).
{| class="wikitable sortable"
|EXAMPLE: Common  (Oligodendroglioma)
|EXAMPLE: D,  P
|
|
|-
|-
|EXAMPLE:
!Chromosomal Pattern
 
!Molecular Pathogenesis
Microsatellite  instability - hypermutated
!Prevalence -  
|
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
|EXAMPLE: Common (Endometrial carcinoma)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
|EXAMPLE: P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
|
!Clinical Relevance Details/Other Notes
|
|-
|-
|
|N/A
|
|
|
|
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|
|
|}
|}
 
==Gene Mutations (SNV/INDEL)==
 
'''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
{| class="wikitable"
{| class="wikitable"
|'''Gene'''
|'''Gene'''
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|'''Tumor Suppressor Gene (TSG)/Oncogene/Other'''
|'''Tumor Suppressor Gene (TSG)/Oncogene/Other'''
|'''Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
|'''Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
|'''Diagnostic, Prognostic, and Therapeutic  Significance - D, P, T'''  
|'''Diagnostic, Prognostic, and Therapeutic  Significance - D, P, T'''
|'''Established Clinical Significance Per  Guidelines - Yes or No (Source)'''
|'''Established Clinical Significance Per  Guidelines - Yes or No (Source)'''
|'''Clinical Relevance Details/Other Notes'''
|'''Clinical Relevance Details/Other Notes'''
|-
|-
|''FLT3-ITD''
|''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''<ref name=":4" />
|-
|-
|''WT1''
|''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''<ref name=":4" />
|-
|''KRAS''
|Gain of function
|Oncogene
|Recurrent
|
|
|
|No
|
|
|
|
|-
|-
|''RB1''
|''NRAS''
|
|Gain of function
|
|Oncogene
|
|Recurrent
|
|
|
|No
|
|
|}
|}
Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


==Epigenomic Alterations==


Note: A more extensive list of mutations can be found in cBioportal (<nowiki>https://www.cbioportal.org/</nowiki>), COSMIC (<nowiki>https://cancer.sanger.ac.uk/cosmic</nowiki>), ICGC (<nowiki>https://dcc.icgc.org/</nowiki>) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
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'').<ref name=":4" /><ref name=":5" />
 
==Genes and Main Pathways Involved==
 
{| class="wikitable sortable"
'''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.'')                                                      
{| class="wikitable"
|'''Gene; Genetic Alteration'''
|'''Pathway'''
|'''Pathophysiologic Outcome'''
|-
|-
|EXAMPLE: ''BRAF'' and ''MAP2K1''; Activating mutations
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|EXAMPLE: MAPK signaling
|EXAMPLE: Increased cell growth and proliferation
|-
|-
|EXAMPLE: ''CDKN2A''; Inactivating mutations
|Various ''NUP98'' fusions
|EXAMPLE: Cell cycle regulation
|HOX-family pathways
|EXAMPLE: Unregulated cell division
|Disruption of critical hematopoietic regulator; dysregulation of differentiation, proliferation, apoptosis, and cell survival.<ref name=":3">{{Cite journal|last=Rasouli|first=Milad|last2=Troester|first2=Selina|last3=Grebien|first3=Florian|last4=Goemans|first4=Bianca F.|last5=Zwaan|first5=C. Michel|last6=Heidenreich|first6=Olaf|date=2024-09|title=NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities|url=https://pubmed.ncbi.nlm.nih.gov/39323480|journal=HemaSphere|volume=8|issue=9|pages=e70013|doi=10.1002/hem3.70013|issn=2572-9241|pmid=39323480}}</ref>
|-
|EXAMPLE: ''KMT2C'' and ''ARID1A''; Inactivating mutations
|EXAMPLE: Histone modification, chromatin remodeling
|EXAMPLE:  Abnormal gene expression  program
|-
|
|
|
|}
|}
==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.<ref name=":5" /><ref name=":1" /> The following techniques may be used to facilitate detection of cryptic rearrangements:


'''Genetic Diagnostic Testing Methods'''
*FISH (e.g. locus-specific ''NUP98'' break-apart probe)
 
*RT-PCR assays for detection of specific fusions
·        FISH using NUP98 break-apart probes
*RNA sequencing
 
*Optical genome mapping<br />
·        RT-PCR for fusion proteins like NUP98::NSD1
[[File:NUP98 NSD1 OGM panel figure.png|none|thumb|617x617px|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''.]]
 
·        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'''
==Familial Forms==


Put a link here or anywhere appropriate in this page (''Instructions: Highlight the text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the wiki page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "<nowiki>http://www</nowiki>." portion.'')
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).<ref name=":2" /><ref name=":3" />


'''References'''
==Links==


Not applicable.
==References==
<references />


'''Notes'''
==Notes==
<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] 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.


<nowiki>*</nowiki>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 [[Leadership|''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): 


Prior Author(s):  
       
<br />
<nowiki>*</nowiki>''Citation of this Page'': “Acute myeloid leukaemia with NUP98 rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NUP98_rearrangement</nowiki>.
[[Category:HAEM5]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases A]]
[[Category:Diseases A]]

Latest revision as of 11:50, 31 December 2025


Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Eric McGinnis, MD, Vancouver General Hospital

Fatma Albulushi, MD, University Medical City

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.[1] 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.[2][3] NUP98 fusion proteins typically involve the N-terminal portion of NUP98 and the C-terminal portion of the fusion partner.[2] 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.[4]

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.[5]
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). [5]
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[2] 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[3]
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[3]
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).[3][1]

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.[6]

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.[1][5] 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).[2][6]

Links

Not applicable.

References

  1. ↑ 1.0 1.1 1.2 Patkar N, Meshinchi S, Westerman D, et al. Acute myeloid leukaemia with NUP98 rearrangement. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours. Lyon (France): International Agency for Research on Cancer; 2024. . (WHO classification of tumours series, 5th ed.; vol. 11). https://publications.iarc.who.int/637.
  2. ↑ 2.0 2.1 2.2 2.3 Gough, Sheryl M.; et al. (2011-12-08). "NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights". Blood. 118 (24): 6247–6257. doi:10.1182/blood-2011-07-328880. ISSN 1528-0020. PMC 3236115. PMID 21948299.
  3. ↑ 3.0 3.1 3.2 3.3 Michmerhuizen, Nicole L.; et al. (2020-11-12). "Mechanistic insights and potential therapeutic approaches for NUP98-rearranged hematologic malignancies". Blood. 136 (20): 2275–2289. doi:10.1182/blood.2020007093. ISSN 1528-0020. PMC 7702474 Check |pmc= value (help). PMID 32766874 Check |pmid= value (help).
  4. ↑ 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)
  5. ↑ 5.0 5.1 5.2 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.
  6. ↑ 6.0 6.1 Rasouli, Milad; et al. (2024-09). "NUP98 oncofusions in myeloid malignancies: An update on molecular mechanisms and therapeutic opportunities". HemaSphere. 8 (9): e70013. doi:10.1002/hem3.70013. ISSN 2572-9241. PMID 39323480 Check |pmid= value (help). Check date values in: |date= (help)

Notes

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*Citation of this Page: “Acute myeloid leukaemia with NUP98 rearrangement”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/31/2025, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NUP98_rearrangement.

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