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==Primary Author(s)*==

Jessica Snider, M.D. and Daynna J. Wolff, Ph.D.

__TOC__

==Cancer Category/Type==

Acute Myeloid Leukemia

==Cancer Sub-Classification / Subtype==

NUP214/ABL1-Mediated Acute Myelomonocytic Leukemia

==Definition / Description of Disease==

A hematologic neoplasm comprised of myeloblasts that arise from the bone marrow due to amplification at 9q that has breakpoints in the ''ABL1'' and ''NUP214'' gene, resulting in a ''NUP214''-''ABL1'' gene fusion. ''NUP214'' is required for cell cycle and nucleocytoplasmic transport. The NUP214-ABL1 protein cannot activate the ABL1 tyrosine kinase unless it interacts and competes with other nuclear pore proteins and thus, the amplification of ''NUP214''-''ABL1'' is necessary for neoplastic transformation and results in a constitutively activated tyrosine kinase with oncogenic potential<ref name=":0">{{Cite journal|last=Zhou|first=Min-Hang|last2=Yang|first2=Qing-Ming|date=2014|title=NUP214 fusion genes in acute leukemia (Review)|url=https://www.ncbi.nlm.nih.gov/pubmed/25120641|journal=Oncology Letters|volume=8|issue=3|pages=959–962|doi=10.3892/ol.2014.2263|issn=1792-1074|pmc=4114590|pmid=25120641}}</ref><ref name=":1">{{Cite journal|last=Duployez|first=Nicolas|last2=Grzych|first2=Guillaume|last3=Ducourneau|first3=Benoît|last4=Fuentes|first4=Martin Alarcon|last5=Grardel|first5=Nathalie|last6=Boyer|first6=Thomas|last7=Chahla|first7=Wadih Abou|last8=Bruno|first8=Bénédicte|last9=Nelken|first9=Brigitte|date=2016|title=NUP214-ABL1 fusion defines a rare subtype of B-cell precursor acute lymphoblastic leukemia that could benefit from tyrosine kinase inhibitors|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004396/|journal=Haematologica|volume=101|issue=4|pages=e133–e134|doi=10.3324/haematol.2015.136499|issn=0390-6078|pmc=5004396|pmid=26681761}}</ref>. This gene fusion has recently been identified in one case of acute myeloid leukemia (AML), and prognosis has yet to be determined in this single case.

==Synonyms / Terminology==

Acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia

==Epidemiology / Prevalence==

One case of NUP214/ABL1-Mediated Acute Myelomonocytic Leukemia has been identified in a 64 year old male after initial treatment with FLT3-directed therapy. This translocation has also been observed in ~6% of all T-cell Acute Lymphoblastic Leukemias and only a few cases of B-cell Acute Lymphoblastic Leukemias<ref name=":0" />.

==Clinical Features==

Fatigue, insomnia, dizziness, splenomegaly

==Sites of Involvement==

Peripheral blood and bone marrow

==Morphologic Features==

Leukocytosis consisting of blast-like cells with a high nuclear to cytoplasm ratio and open chromatin as well as mature monocytes can be observed in the peripheral smear. In the bone marrow, the myeloid series consists mostly of blast-like cells with minimal evidence of terminal differentiation. Rare erythroid elements and megakaryocytes may be seen.

==Immunophenotype==

Myeloblasts express dim CD45, dim CD34, dim CD117, HLA-DR, dim CD33, and dim CD13.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||EXAMPLE CD1
|-
|Positive (subset)||EXAMPLE CD2
|-
|Negative (universal)||EXAMPLE CD3
|-
|Negative (subset)||EXAMPLE CD4
|}

==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and/or fill in the table

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
| ||3'ABL1 / 5'NUP214|| ||Rare
|-
|}

==Characteristic Chromosomal Aberrations / Patterns==

Put your text here

==Genomic Gain/Loss/LOH==

Put your text here and/or fill in the table

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|9q||Amp||Chr9:133728488-134083915
|-
|}

Additional findings in our case (may or may not be related to NUP214-ABL1 gene fusion):
{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|11q||LOH||Chr11:66206967-135006516
|-
|11q||Amp LOH||Chr11:118335673-118357315
|-
|21q||Loss||Chr21:36209650-36315003
|}

==Gene Mutations (SNV/INDEL)==

In addition to the NUP214-ABL1 gene fusion, the single case identified showed focal deletion of exons 3-8 of RUNX1, loss of heterozygosity of 11q with nested gain of exons 2-10 of the KMT2A (MLL) gene. It is unknown whether or not these additional findings are related to the NUP214-ABL1 gene fusion.

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
|}

===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||EXAMPLE IDH1 R123H
|-
|Secondary Mutations||EXAMPLE Trisomy 7
|-
|Mutually Exclusive||EXAMPLE EGFR Amplification
|}

==Epigenomics (Methylation)==

Not applicable.

==Genes and Main Pathways Involved==

NUP214 (nucleoporin 214) is required for cell cycle and nucleocytoplasmic transport. The protein is located on the cytoplasmic side of the nuclear pore complex. The gene is located at band 9q34.1 and includes 36 exons (1-36). The NUP214-ABL1 protein cannot activate the ABL1 kinase unless it interacts and competes with other nuclear pore proteins and thus, the amplification of NUP214-ABL1 is necessary for neoplastic transformation, resulting in a constitutively activated tyrosine kinase with oncogenic potential<ref name=":0" /><ref name=":1" />.

RUNX1 is a transcription factor that regulates the differentiation of hematopoietic stem cells into mature blood cells. RUNX proteins form a heterodimeric complex with CBFβ which confers increased DNA binding and stability to the complex.

KMT2A encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis.

==Diagnostic Testing Methods==

Classical cytogenetics, FISH and molecular genetics.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

No data has been reported on the prognosis of a NUP214-ABL1 fusion in AML. RUNX1 deletions have been reported to be an independent marker for a shorter event free survival, having a decreased overall survival and demonstrate resistance to chemotherapy<ref>{{Cite journal|last=Takahashi|first=Shinichiro|date=2011|title=Current findings for recurring mutations in acute myeloid leukemia|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180439/|journal=Journal of Hematology & Oncology|volume=4|pages=36|doi=10.1186/1756-8722-4-36|issn=1756-8722|pmc=3180439|pmid=21917154}}</ref>. The presence of a partial tandem duplication of the KMT2A gene has been reported to have an overall unfavorable prognosis with shorter remission with relapse generally occurring in the first year<ref>{{Cite journal|last=Schnittger|first=S.|last2=Kinkelin|first2=U.|last3=Schoch|first3=C.|last4=Heinecke|first4=A.|last5=Haase|first5=D.|last6=Haferlach|first6=T.|last7=Büchner|first7=T.|last8=Wörmann|first8=B.|last9=Hiddemann|first9=W.|date=2000|title=Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML|url=https://www.ncbi.nlm.nih.gov/pubmed/10803509|journal=Leukemia|volume=14|issue=5|pages=796–804|doi=10.1038/sj.leu.2401773|issn=0887-6924|pmid=10803509}}</ref>.

==Familial Forms==

No familial forms have been documented.

==Other Information==

Put your text here

==Links==

[[ABL1]]

[[NUP214]]

==References==
<references />

==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.

[[Category:Translocation]]
[[Category:Translocation Chromosome 9]]
[[Category:Structural Chromosome Abnormalities]]
[[Category:Structural Chromosome Abnormalities in AML]]
[[Category:Structural Abnormalities Chromosome 9]]
[[Category:Fusion Genes in AML]]
[[Category:Fusion Genes A]]
[[Category:Fusion Genes N]]
[[Category:Recently Added Pages]]

HAEM4Backup:Acute Myeloid Leukemia (AML) with NUP214-ABL1 - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Jessica Snider, M.D. and Daynna J. Wolff, Ph.D. __TOC__ ==Cancer Category/Type== Acute Myeloid Leukemia ==Cancer Sub-Classification / Subtype== N..."

Bailey.Glen: Created page with "==Primary Author(s)*== Jessica Snider, M.D. and Daynna J. Wolff, Ph.D. TOC ==Cancer Category/Type== Acute Myeloid Leukemia ==Cancer Sub-Classification / Subtype== N..."