Compendium of Cancer Genome Aberrations

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HAEM5:Acute myeloid leukaemia with NUP98 rearrangement (view source)

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{{DISPLAYTITLE:Acute myeloid leukaemia with NUP98 rearrangement}}
 
{{DISPLAYTITLE:Acute myeloid leukaemia with NUP98 rearrangement}}
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
 
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
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==Primary Author(s)*==
 
==Primary Author(s)*==
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Put your text here<span style="color:#0070C0"> (''<span class="blue-text">EXAMPLE:</span>'' Jane Smith, PhD) </span>
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Eric McGinnis, MD
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Fatma Albulushi, MD
    
__TOC__
 
__TOC__
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|Acute myeloid leukaemia with NUP98 rearrangement
 
|Acute myeloid leukaemia with NUP98 rearrangement
 
|}
 
|}
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==WHO Essential and Desirable Genetic Diagnostic Criteria.==
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{| class="wikitable"
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|WHO Essential Criteria  (Genetics)*
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|Detection of NUP98 rearrangement
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|-
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|WHO Desirable Criteria  (Genetics)*
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|Identification of the NUP98 fusion  partner
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|-
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|Other Classification
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|Myeloid blast count may <20%
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|}
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<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.
    
==Definition / Description of Disease==
 
==Definition / Description of Disease==
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==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
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Put your text here and fill in the table
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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>
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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>
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<br />
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{| class="wikitable"
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|'''Driver Gene'''
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|'''Fusion(s) and Common Partner Genes'''
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|'''Molecular Pathogenesis'''
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|'''Typical Chromosomal Alteration(s)'''
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|'''Prevalence -Common >20%, Recurrent  5-20% or Rare <5% (Disease)'''
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|'''Diagnostic,  Prognostic, and Therapeutic Significance - D, P, T'''
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|'''Established  Clinical Significance Per Guidelines - Yes or No (Source)'''
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|'''Clinical  Relevance Details/Other Notes'''
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|-
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|''NUP98''
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|''NUP98::NSD1''
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<br />
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|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.
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|t(5;11)(q35;p15)
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Usually cryptic
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|Rare (AML)
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|Defining genetic abnormality in AML
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|Yes (WHO)
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|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" />
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|-
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|''NUP98''
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|''NUP98::KDM5A''
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|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.
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|t(11;12)(p15;p13)
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Usually cryptic
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|Rare (AML)
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|Defining genetic abnormality in AML
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|Yes (WHO)
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|''Commonly associated with erythroid and megakaryocytic phenotypes  in pediatric AML (acute erythroid leukemia and acute megakaryocytic  leukemia).''<ref name=":1" />
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''Usually associate with unfavorable outcomes''
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|-
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|''NUP98''
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|''NUP98::HOXA9''
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<br />
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|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.
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|t(7;11)(p15, p15)
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|Rare (AML)
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|Defining genetic abnormality in AML
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|
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|
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|}
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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==Individual Region Genomic Gain / Loss / LOH==
 
==Individual Region Genomic Gain / Loss / LOH==
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No characteristic chromosomal gain or loss. However, trisomy 8 and chromosome 13 abnormalities may be observed.
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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.
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<br />
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{| class="wikitable"
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|'''Chromosome Number'''
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|'''Gain/Loss/Amp/LOH'''
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|'''Minimal Region Cytoband and/or Genomic  Coordinates [Genome Build; Size]'''
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|'''Relevant Gene(s)'''
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|'''Diagnostic,  Prognostic, and Therapeutic Significance - D, P, T'''
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|'''Established  Clinical Significance Per Guidelines - Yes or No (Source)'''
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|'''Clinical  Relevance Details/Other Notes'''
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|-
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|8
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|Gain
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|Trisomy 8
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|Unknown
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|NA
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|No
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|
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|-
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|13
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|loss
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|Deletion of 13q
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|RB1 gene
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|NA
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|
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|Particularly associated with NUP98::KDM5A
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|}
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
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{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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|}
 
==Gene Mutations (SNV / INDEL)==
 
==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
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{| class="wikitable"
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|'''Gene'''
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|'''Genetic Alteration'''
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|'''Tumor Suppressor Gene (TSG)/Oncogene/Other'''
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|'''Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
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|'''Diagnostic, Prognostic, and Therapeutic  Significance - D, P, T'''
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|'''Established Clinical Significance Per  Guidelines - Yes or No (Source)'''
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|'''Clinical Relevance Details/Other Notes'''
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|-
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|''FLT3-ITD''
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|
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|
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|Recurrent
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|Poor prognosis
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|
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|Seen in 67  to 91% of cases with NUP98::NSD1
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|-
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|''WT1''
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|
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|
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|Rare
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|
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|
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|Reported in  33-55% of NUP98::NSD1 rearranged AML
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|-
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|''RB1''
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|
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|
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|Rare
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|
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|
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|Particularly associated with  NUP98::KDM5A
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|}
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Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>
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==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
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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:
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* FISH using NUP98 break-apart probes
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* RT-PCR for fusion proteins like NUP98::NSD1
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* RNA sequencing
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* Optical Genome Mapping (OGM)
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<br />
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[[File:NUP98 NSD1.png|none|thumb|617x617px|Karyotype image of NUP98 rearranged acute myeloid leukemia. Due to the cryptic nature of NUP98 rearrangement, karyotype is usually normal. ]]
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[[File:T(5;11).jpg|none|thumb|584x584px|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.]]
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<br />
    
==Familial Forms==
 
==Familial Forms==
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==Additional Information==
 
==Additional Information==
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<br />
    
==Links==
 
==Links==
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<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<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>.
 
<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>.
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[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]
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[[Category:HAEM5]]
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[[Category:DISEASE]]
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[[Category:Diseases A]]
Retrieved from "https://ccga.io/index.php/Special:MobileDiff/15556...15561"