View source for HAEM4:Acute Myeloid Leukemia (AML) with t(6;9)(p23;q34.1); DEK-NUP214

{{DISPLAYTITLE:Acute Myeloid Leukemia (AML) with t(6;9)(p23;q34.1); DEK-NUP214}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
==Primary Author(s)*==

Jennelle C. Hodge, PhD, FACMG

__TOC__

[[File:T(6;9)(p23;q34).png]]

==Cancer Category/Type==

[[AML|Acute Myeloid Leukemia]]

==Cancer Sub-Classification / Subtype==

Acute myeloid leukemia (AML) with t(6;9)(p23;q34.1) resulting in DEK-NUP214 fusion

==Definition / Description of Disease==

This is a distinct entity in the World Health Organization (WHO) classification system, and the most common associated French-American-British (FAB) classifications are M2, M4 and M1<ref name=":0">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, p137-138.</ref><ref>{{Cite journal|last=Oyarzo|first=Mauricio P.|last2=Lin|first2=Pei|last3=Glassman|first3=Armand|last4=Bueso-Ramos|first4=Carlos E.|last5=Luthra|first5=Rajyalakshmi|last6=Medeiros|first6=L. Jeffrey|date=2004|title=Acute myeloid leukemia with t(6;9)(p23;q34) is associated with dysplasia and a high frequency of flt3 gene mutations|url=https://www.ncbi.nlm.nih.gov/pubmed/15362364|journal=American Journal of Clinical Pathology|volume=122|issue=3|pages=348–358|doi=10.1309/5DGB-59KQ-A527-PD47|issn=0002-9173|pmid=15362364}}</ref>. 

==Synonyms / Terminology==

None

==Epidemiology / Prevalence==

Accounts for 0.7-1.8% of AML, occurring in both children (median age of 13 years) and adults (median age of 35-44 years)<ref name=":0" />.

==Clinical Features==

Usually presents with anemia and thrombocytopenia and often with pancytopenia.  In adults, the median white blood cell count is 12x10^9/L, which is generally lower than other AML types<ref name=":0" />.

==Sites of Involvement==

Bone marrow

==Morphologic Features==

This AML subtype may present with or without monocytic features and is frequently associated with basophilia (44-62% of cases) and multilineage dysplasia (most commonly granulocytic and erythroid, and less often megakaryocytic dysplasia)<ref name=":0" />.  Auer rods occur in ~1/3 of cases and ringed sideroblasts may also occur<ref name=":0" />.  The peripheral blood or bone marrow have >20% blasts characterized by a non-specific myeloid immunophenotype<ref name=":0" />.

==Immunophenotype==

The characteristic immunophenotype of the blasts associated with this entity is listed in the table below.  In addition, basophils may present as separate clusters of CD123+, CD33+ CD38+ and HLA-DR- cells<ref name=":0" />.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Myeloperoxidase (MPO), CD9, CD13, CD33, CD38 CD123, and HLA-DR
|-
|Positive (subset)||KIT(CD117), CD34, CD15, CD64 (monocyte-associated marker), and Dexoynucleotidyl Transferase (TdT)
|-
|Negative (universal)||
|-
|Negative (subset)||
|}

==Chromosomal Rearrangements (Gene Fusions)==

This AML subtype is classified based on the presence of a t(6;9)(p23;q34.1), which results in fusion of the 5’ portion of ''DEK'' at “6p23” (specifically 6p22.3[hg38]) and the 3’ portion of ''NUP214''(''CAN'') at “9q34.1” (specifically 9q34.13[hg38]).  The breakpoints are intronic, producing an in-frame fusion<ref>{{Cite journal|last=von Lindern|first=M.|last2=Fornerod|first2=M.|last3=van Baal|first3=S.|last4=Jaegle|first4=M.|last5=de Wit|first5=T.|last6=Buijs|first6=A.|last7=Grosveld|first7=G.|date=1992|title=The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA|url=https://www.ncbi.nlm.nih.gov/pubmed/1549122|journal=Molecular and Cellular Biology|volume=12|issue=4|pages=1687–1697|doi=10.1128/mcb.12.4.1687|issn=0270-7306|pmc=PMC369612|pmid=1549122}}</ref>.  The ''DEK''-''NUP214'' fusion present on the derivative chromosome 6 is considered the pathogenic entity as the reciprocal ''NUP214''-''DEK'' fusion on chromosome 9 does not appear to be transcribed<ref>{{Cite journal|last=von Lindern|first=M.|last2=Fornerod|first2=M.|last3=Soekarman|first3=N.|last4=van Baal|first4=S.|last5=Jaegle|first5=M.|last6=Hagemeijer|first6=A.|last7=Bootsma|first7=D.|last8=Grosveld|first8=G.|date=1992|title=Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene|url=https://www.ncbi.nlm.nih.gov/pubmed/1308167|journal=Bailliere's Clinical Haematology|volume=5|issue=4|pages=857–879|doi=10.1016/s0950-3536(11)80049-1|issn=0950-3536|pmid=1308167}}</ref>.  Typically the ''DEK''-''NUP214'' fusion presents as the sole abnormality but can be part of a complex karyotype<ref name=":0" />.

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|t(6;9)(p23;q34.1)||5'DEK / 3'NUP214(CAN)||der(6)||0.7-1.8% of AML
|-
|}

==Characteristic Chromosomal Aberrations / Patterns==

Not applicable

==Genomic Gain/Loss/LOH==

Not applicable
		
==Gene Mutations (SNV/INDEL)==

COSMIC does not have specific information on mutations related to this subtype of AML.

===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||FLT3-ITD (69% of children and 78% of adults)
|-
|Secondary Mutations||
|-
|Mutually Exclusive||FLT3-TKD is very uncommon
|}

==Epigenomics (Methylation)==

Not applicable

==Genes and Main Pathways Involved==

The molecular mechanism is not completely understood, but the fusion protein is known to act as an aberrant transcription factor, alter nuclear transport and induce myeloid cell-specific global protein synthesis<ref name=":0" /><ref>{{Cite journal|last=Ageberg|first=Malin|last2=Drott|first2=Kristina|last3=Olofsson|first3=Tor|last4=Gullberg|first4=Urban|last5=Lindmark|first5=Anders|date=2008|title=Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis|url=https://www.ncbi.nlm.nih.gov/pubmed/18181180|journal=Genes, Chromosomes & Cancer|volume=47|issue=4|pages=276–287|doi=10.1002/gcc.20531|issn=1098-2264|pmid=18181180}}</ref>.

==Diagnostic Testing Methods==

Karyotype, FISH, RT-PCR

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

This translocation has traditionally been associated with a poor prognosis in both adult and pediatric cases<ref name=":0" />.  Of note, a 2014 retrospective analysis suggests a better outcome for pediatric patients with this translocation than previously reported<ref>{{Cite journal|last=Sandahl|first=Julie Damgaard|last2=Coenen|first2=Eva A.|last3=Forestier|first3=Erik|last4=Harbott|first4=Jochen|last5=Johansson|first5=Bertil|last6=Kerndrup|first6=Gitte|last7=Adachi|first7=Souichi|last8=Auvrignon|first8=Anne|last9=Beverloo|first9=H. Berna|date=2014|title=t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients|url=https://www.ncbi.nlm.nih.gov/pubmed/24441146|journal=Haematologica|volume=99|issue=5|pages=865–872|doi=10.3324/haematol.2013.098517|issn=1592-8721|pmc=4008104|pmid=24441146}}</ref>.  Elevated white blood cell counts and higher bone marrow blast percentages are associated with shorter periods of overall survival and disease-free survival, respectively<ref name=":0" />.

Limited data suggests early allogeneic stem cell transplantation may be associated with better overall survival compared to patients without transplantation, suggesting accurate diagnosis for these patients is crucial<ref name=":0" /><ref>{{Cite journal|last=Slovak|first=M. L.|last2=Gundacker|first2=H.|last3=Bloomfield|first3=C. D.|last4=Dewald|first4=G.|last5=Appelbaum|first5=F. R.|last6=Larson|first6=R. A.|last7=Tallman|first7=M. S.|last8=Bennett|first8=J. M.|last9=Stirewalt|first9=D. L.|date=2006|title=A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare 'poor prognosis' myeloid malignancies|url=https://www.ncbi.nlm.nih.gov/pubmed/16628187|journal=Leukemia|volume=20|issue=7|pages=1295–1297|doi=10.1038/sj.leu.2404233|issn=0887-6924|pmid=16628187}}</ref><ref>{{Cite journal|last=Ishiyama|first=K.|last2=Takami|first2=A.|last3=Kanda|first3=Y.|last4=Nakao|first4=S.|last5=Hidaka|first5=M.|last6=Maeda|first6=T.|last7=Naoe|first7=T.|last8=Taniguchi|first8=S.|last9=Kawa|first9=K.|date=2012|title=Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with t(6;9)(p23;q34) dramatically improves the patient prognosis: a matched-pair analysis|url=https://www.ncbi.nlm.nih.gov/pubmed/21869835|journal=Leukemia|volume=26|issue=3|pages=461–464|doi=10.1038/leu.2011.229|issn=1476-5551|pmid=21869835}}</ref>.

The concurrent presence of FLT3-ITD does not appear to negatively impact survival in the pediatric population<ref name=":0" />.

Cases with the 6;9 translocation and <20% blasts are not currently classified as AML, which is controversial.  Such cases should have close follow-up to monitor for development of more definitive evidence of AML or may be treated as AML if clinically appropriate<ref name=":0" />.

==Familial Forms==

Not applicable

==Other Information==

Not applicable

==Links==

[[DEK]]

[[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:HAEM4]] [[Category:DISEASE]]