Compendium of Cancer Genome Aberrations

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

(View all pending changes)
[pending revision][pending revision]
← Older edit
VisualWikitext
Content added
No edit summary
 
(22 intermediate revisions by 4 users not shown)
Line 4: Line 4:


{{Under Construction}}
{{Under Construction}}
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 to a table, click within the table and select the > symbol that appears to be given options. 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>


==Primary Author(s)*==
==Primary Author(s)*==


Eric McGinnis, MD
Eric McGinnis, MD, Vancouver General Hospital
 
Fatma Albulushi, MD
 
__TOC__


Fatma Albulushi, MD, University Medical City
==WHO Classification of Disease==
==WHO Classification of Disease==


Line 37: Line 32:
|}
|}


== WHO Essential and Desirable Genetic Diagnostic Criteria. ==
==Related Terminology==
{| 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.
 
==Definition / Description of Disease==
 
Put your text here <span style="color:#0070C0">(''Instructions: Brief description of approximately one paragraph - include disease context relative to other WHO classification categories, diagnostic criteria if applicable, and differential diagnosis if applicable. Other classifications can be referenced for comparison.'') </span>
 
==Synonyms / Terminology==


Put your text here <span style="color:#0070C0">(''Instructions: Include currently used terms and major historical ones, adding “(historical)” after the latter.'') </span>
==Epidemiology / Prevalence==
Put your text here
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|N/A
<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
 
<span class="blue-text">EXAMPLE:</span> Fatigue
 
<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias
 
<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}
 
==Sites of Involvement==
 
Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; <span class="blue-text">EXAMPLE:</span> nodal, extranodal, bone marrow'') </span>
 
==Morphologic Features==
 
Put your text here
 
==Immunophenotype==
 
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
 
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
|-
|-
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
|Not Recommended
|-
|N/A
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
|-
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> CD4
|}
|}


==Chromosomal Rearrangements (Gene Fusions)==
==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>
 
 
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'''
Line 119: Line 51:
|'''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 125: 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)


Line 132: Line 63:
|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 143: 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" />
 
''Usually associate with 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)
|
|
|}
|}
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Yes
|No
|Yes
|<span class="blue-text">EXAMPLE:</span>


The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
==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.
<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 195: 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
|
|Particularly associated with NUP98::KDM5A
|}
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>
{| class="wikitable sortable"
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>
chr8
|No
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>
|Highly enriched in ''NUP98::KDM5A''
 
Common recurrent secondary finding for t(8;21) (add reference).
|}
|}
==Characteristic Chromosomal Patterns==
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: 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. Do not delete table.'')</span>


==Characteristic Chromosomal or Other Global Mutational Patterns==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosomal Pattern
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Molecular Pathogenesis
!Prognostic Significance (Yes, No or Unknown)
!Prevalence -
!Therapeutic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Notes
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|N/A
 
|
Co-deletion of 1p and 18q
|
|Yes
|
|No
|
|No
|
|<span class="blue-text">EXAMPLE:</span>
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
|}
==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'''
Line 279: Line 138:
|'''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
|Recurrent-Common (frequency varies with fusion partner)
|Poor prognosis 
|P,T
|
|Yes (ELN 2022; independent of fusion)
|Seen in 67  to 91% of cases with NUP98::NSD1
|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
|Rare
|High frequency in AML with ''NUP98::NSD1;'' reported association with adverse prognosis specifically in context of ''NUP98::NSD1''<ref name=":4" />
|
|
|Reported in 33-55% of NUP98::NSD1 rearranged AML
|-
|-
|''RB1''
|''KRAS''
|Gain of function
|Oncogene
|Recurrent
|
|
|No
|
|
|Rare
|
|
|Particularly associated with  NUP98::KDM5A
|}
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>
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
|''NRAS''
!'''Diagnostic Significance (Yes, No or Unknown)'''
|Gain of function
!Prognostic Significance (Yes, No or Unknown)
|Oncogene
!Therapeutic Significance (Yes, No or Unknown)
|Recurrent
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
 
<span class="blue-text">EXAMPLE:</span>
 
EGFR; Exon 20 mutations
 
<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
 
<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|No
|
|
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
|}
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.
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==
==Epigenomic Alterations==


Put your text here
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==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|Various ''NUP98'' fusions
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|HOX-family pathways
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|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>
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


·        FISH using NUP98 break-apart probes
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:


·        RT-PCR for fusion proteins like NUP98::NSD1
*FISH (e.g. locus-specific ''NUP98'' break-apart probe)
 
*RT-PCR assays for detection of specific fusions
·        RNA sequencing
*RNA sequencing
 
*Optical genome mapping<br />
·        Optical Genome Mapping (OGM)
[[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''.]]


==Familial Forms==
==Familial Forms==


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
Not applicable.
 
==Additional Information==
==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.
''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" />


==Links==
==Links==


Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the 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.'')</span>
Not applicable.
 
==References==
==References==
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
<references />


'''EXAMPLE Book'''
==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.


#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
Prior Author(s):


==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 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>.
[[Category:HAEM5]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases A]]
[[Category:Diseases A]]
Retrieved from "https://test.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_NUP98_rearrangement"