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t(6;9)(p22;q34) DEK/NUP214

Identity

Note The translocation, known as t(6;9)(p23;q34), has been renamed t(6;9)(p22;q34), since DEK sits in 6p22.3
 
  t(6;9)(p23;q34) G- banding (left)- Courtesy Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap Cytogenetics at the Waisman Center (top and middle top), Jean-Luc Lai (middle below), and Roland Berger (below); and R- banding - Courtesy Lucienne Michaux (top 2); and Courtesy Christine Pérot (bottom 2).

Clinics and Pathology

Disease Acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS)
Phenotype / cell stem origin Altogether, 191 cases are available: 110 cases extracted from the Mitelman database (Cases quick searcher + Molecular biology associations searcher), cases from Garçon et al., 2005, and cases from the largest study to date (69 cases) (Slovak et al., 2006).
The WHO/FAB classification was: M1-AML: 13% (25/191 cases), M2-AML: 34% (64/191), M1/M2-AML: 1% (2 cases), M4-AML: 24% (45/191), M5-AML: 2% (4 cases), M6-AML: 2% (3 cases), AML not otherwise specified (26 cases), refractory anemia with excess of blasts (RAEB): 7% (13/191), chronic myelogenous leukemia (CML): 2% (3 cases), other myelodysplastic and/or myeloproliferative syndrome: 2% (3 cases), acute basophilic leukemia: 1 case, unknown: 2 cases. Acute myeloid leukemia is often preceded by an episode of myelodysplastic syndrome. The t(6;9) may be secondary to toxic exposure; in some instances.
In the t(6;9), long-term (Sca1+/c-Kit+/lin- /Flk2-) hematopoietic stem cells (LT-HSC) appear to be the leukemia-initiating cells, while leukemia-maintaining cells represent a larger and phenotypically heterogeneous cell population (Oancea et al., 2010).
Epidemiology The t(6;9) is found in about 1% of AMLs (0.9% in the series of 69 cases, with a repartition of 1.4% in children AMLs, and 0.7% in adult cases (Slovak et al., 2006)); from this study, median age was 23 years (range 2-66 years), with 30 children out of 69 cases (43%), a younger age than in AML in general. From 199 cases herein reviewed, the sex ratio is balanced: 1M/1F (100 male patients and 99 female patients).
Cytology TdT +, HLA-DR, CD13, CD33, CD38, CD45 and CD117; frequent expression of CD9, CD15, CD34 Auer rods are frequently observed. Blood data: a marked basophilia is frequent (found in 44% of the patients in Slovak et al., 2006). Granulocytic, megakaryocytic, or multilineage dysplasia was found in two third of adult cases in the same report.
 
The translocation t(6;9)(p23;q34) results in the formation of a chimeric fusion gene: DEK (6q23) and CAN (9q34). CAN is a putative oncogene which may be activated by fusion of its 3' end to other genes than DEK. One such recently reported gene is called SET and leads to expression of a SET/CAN fusion RNA. The t(6;9)(p21-22;q34) may be seen in either AML M2 or less frequently in M4 or MDS and acute myelofibrosis often in association with excessz basophils. The t(6;9) is reported mostly in young adults. The prognosis of patients carrying the t(6;9) is unfavorable - Text and iconography Courtesy Georges Flandrin 2005.
 
Overall survival in patients with t(6;9)(p23;q34) (adapted from Slovak et al., 2006): 31 children cases, 32 adult cases, compared with 174 young adult AML in the unfavorable risk cytogenetics subgroup.
Treatment Allogeneic stem cell transplantation might be associated with better outcome (Slovak et al., 2006).
Prognosis Overall, 65% of patients, 71% of pediatric cases and 58% of adults, achieved complete remission (CR) (Slovak et al., 2006). Median survival is around 1 year (12,5 months in children, 14,4 months in adults, 13,5 months altogether). The 5 year overall survival was 28% in children and 9% in adults (see figure) (Slovak et al., 2006). Patients who achieved prolonged molecular remission had better outcome than patients with persistent DEK/NUP214 positivity (Garçon et al., 2005).

Genetics

FLT3 internal tandem duplications was found in 69% of children cases and 73% of adult cases in one study (Slovak et al., 2006), and in 88% of adults cases in another study (Oyarzo et al., 2004). A third study grossly confirm this high incidence (Garçon et al., 2005).

Cytogenetics

Cytogenetics Morphological The t(6;9) may be over loocked.
Additional anomalies The t(6;9) is the sole anomaly in 85% of 195 cases with available data, and in 83% of cases in the largest study (Slovak et al., 2006); recurrent, although rare, additional anomalies are the following: +8 (in 6 of 126 cases, 5%), +13 (in 3 of 126 cases, 2%), +21. A -7/del(7q) was found once, a t(9;22)(q24;q11) once.
Variants A three way complex t(6;9;Var) has been found in 3 instances.

Genes involved and Proteins

Gene Name DEK
Location 6p22.3
Protein 375 amino-acids; DEK contains acidic domains (Asp/Glu-rich), a SAF/SAP box, a nuclear localisation signal; and other DNA binding domains. Highly conserved nuclear factor; chromatin remodeling protein, essential for heterochromatin integrity; DEK localizes preferentially at sites proximal to the promoters of expressed genes; acts as a repressor of transcription by interfering with histone acetyl-transferases and as an activator of transcription by stimulating the binding of TFAP2A (the activator protein AP2-alpha) to its target DNA sequences; DEK introduces super-coils into circular DNA (in Oancea et al., 2010). DEK is a regulator of stem and progenitor cells and is upregulated in a number of neoplasms (breast cancer, chronic lymphocytic leukemia, small cell lung carcinoma, Merkel cell carcinoma, melanoma, glioblastoma, retinoblastoma, cervical, and bladder cancers) (review in Riveiro-Falkenbach and Soengas, 2010); CEBPA and DEK coordinately activate myeloid gene expression (Koleva et al., 2012); DEK is an estrogen receptor alpha (ESR1) target gene (Privette Vinnedge et al., 2012). DEK expression modulates ATM and DNA-dependent protein kinase signaling, and contributes to DNA repair (Kavanaugh et al., 2011).
Gene Name NUP214
Location 9q34
Note The previous name of NUP214 was CAN.
Protein 2090 amino acids; contains dimerization domains (2 leucine zippers) and FG repeats; forms homodimers; the C-terminus is essential; the N-terminus is involved in mRNA export (Köser et al., 2005). Nuclear membrane localisation (cytoplasmic face of nucleopore); component of the nuclear pore complex; involved in nucleo-cytoplasmic transport.

Result of the chromosomal anomaly

Hybrid gene
Description 5' DEK - 3' NUP214 on der(6); head to tail DEK/NUP214 fusion gene (SET/NUP214 exceptional); breakpoint clusters in a single intron of 8 kb (ICB9: 'intron containing breakpoint 9') in NUP214, and in a single intron (of 12 kb) as well (ICB6) in DEK.
Transcript 5.5 kb RNA; no NUP214-DEK reciprocal transcript on chromosome 9.
Detection RNA-PCR.
  
Fusion Protein
Description 165 kDa; N-term with almost the entire DEK protein fused to the C-terminal two-thirds of the NUP214 protein.
Expression Localisation Nuclear localisation.
  

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.

Other genes implicated (Data extracted from papers in the Atlas)

Genes NUP214 DEK

Translocations implicated (Data extracted from papers in the Atlas)

 t(6;9)(p22;q34) DEK/NUP214

External links

Mitelman database Mitelman database (CGAP - NCBI)
t(6;9)(p22;q34) - Mitelman database (CGAP - NCBI)
COSMICHisto = - Site = haematopoietic_and_lymphoid_tissue (COSMIC)
arrayMapTopo ( C42) Morph ( 9865/3) - arrayMap (Zurich)

Bibliography

Increased numbers of marrow basophils may be associated with a t(6;9) in ANLL.
Pearson MG, Vardiman JW, Le Beau MM, Rowley JD, Schwartz S, Kerman SL, Cohen MM, Fleischman EW, Prigogina EL.
Am J Hematol. 1985 Apr;18(4):393-403.
PMID 3976650
 
The (6;9) chromosome translocation, associated with a specific subtype of acute nonlymphocytic leukemia, leads to aberrant transcription of a target gene on 9q34.
von Lindern M, Poustka A, Lerach H, Grosveld G.
Mol Cell Biol. 1990 Aug;10(8):4016-26.
PMID 2370860
 
Dek-can rearrangement in translocation (6;9)(p23;q34).
Soekarman D, von Lindern M, van der Plas DC, Selleri L, Bartram CR, Martiat P, Culligan D, Padua RA, Hasper-Voogt KP, Hagemeijer A, et al.
Leukemia. 1992 Jun;6(6):489-94.
PMID 1602786
 
Translocation t(6;9) in acute non-lymphocytic leukaemia results in the formation of a DEK-CAN fusion gene.
von Lindern M, Fornerod M, Soekarman N, van Baal S, Jaegle M, Hagemeijer A, Bootsma D, Grosveld G.
Baillieres Clin Haematol. 1992 Oct;5(4):857-79. (REVIEW)
PMID 1308167
 
Translocation t(6;9)(p23;q34) in acute myeloid leukemia without myelodysplasia or basophilia: two cases and a review of the literature.
Lillington DM, MacCallum PK, Lister TA, Gibbons B.
Leukemia. 1993 Apr;7(4):527-31. (REVIEW)
PMID 8464230
 
Interaction of cellular proteins with the leukemia specific fusion proteins DEK-CAN and SET-CAN and their normal counterpart, the nucleoporin CAN.
Fornerod M, Boer J, van Baal S, Morreau H, Grosveld G.
Oncogene. 1996 Oct 17;13(8):1801-8.
PMID 8895527
 
Acute myeloid leukemia with t(6;9)(p23;q34) is associated with dysplasia and a high frequency of flt3 gene mutations.
Oyarzo MP, Lin P, Glassman A, Bueso-Ramos CE, Luthra R, Medeiros LJ.
Am J Clin Pathol. 2004 Sep;122(3):348-58.
PMID 15362364
 
DEK-CAN molecular monitoring of myeloid malignancies could aid therapeutic stratification.
Garcon L, Libura M, Delabesse E, Valensi F, Asnafi V, Berger C, Schmitt C, Leblanc T, Buzyn A, Macintyre E.
Leukemia. 2005 Aug;19(8):1338-44.
PMID 15973457
 
The nuclear pore complex becomes alive: new insights into its dynamics and involvement in different cellular processes.
Koser J, Maco B, Aebi U, Fahrenkrog B.
Atlas Genet Cytogenet Oncol Haematol. March 2005. URL: http://AtlasGeneticsOncology.org/Deep/NuclearPoreComplID20048.html
 
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.
Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA, Tallman MS, Bennett JM, Stirewalt DL, Meshinchi S, Willman CL, Ravindranath Y, Alonzo TA, Carroll AJ, Raimondi SC, Heerema NA.
Leukemia. 2006 Jul;20(7):1295-7. Epub 2006 Apr 20.
PMID 16628187
 
The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation.
Oancea C, Ruster B, Henschler R, Puccetti E, Ruthardt M.
Leukemia. 2010 Nov;24(11):1910-9. doi: 10.1038/leu.2010.180. Epub 2010 Sep 9.
PMID 20827285
 
Control of tumorigenesis and chemoresistance by the DEK oncogene.
Riveiro-Falkenbach E, Soengas MS.
Clin Cancer Res. 2010 Jun 1;16(11):2932-8. doi: 10.1158/1078-0432.CCR-09-2330. Epub 2010 May 25. (REVIEW)
PMID 20501624
 
The human DEK oncogene regulates DNA damage response signaling and repair.
Kavanaugh GM, Wise-Draper TM, Morreale RJ, Morrison MA, Gole B, Schwemberger S, Tichy ED, Lu L, Babcock GF, Wells JM, Drissi R, Bissler JJ, Stambrook PJ, Andreassen PR, Wiesmuller L, Wells SI.
Nucleic Acids Res. 2011 Sep 1;39(17):7465-76. doi: 10.1093/nar/gkr454. Epub 2011 Jun 7.
PMID 21653549
 
C/EBPa and DEK coordinately regulate myeloid differentiation.
Koleva RI, Ficarro SB, Radomska HS, Carrasco-Alfonso MJ, Alberta JA, Webber JT, Luckey CJ, Marcucci G, Tenen DG, Marto JA.
Blood. 2012 May 24;119(21):4878-88. doi: 10.1182/blood-2011-10-383083. Epub 2012 Apr 3.
PMID 22474248
 
The DEK oncogene is a target of steroid hormone receptor signaling in breast cancer.
Privette Vinnedge LM, Ho SM, Wikenheiser-Brokamp KA, Wells SI.
PLoS One. 2012;7(10):e46985. doi: 10.1371/journal.pone.0046985. Epub 2012 Oct 10.
PMID 23071688
 
Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (2013).
Mitelman F, Johansson B and Mertens F (Eds.)
http://cgap.nci.nih.gov/Chromosomes/Mitelman
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

Contributor(s)

Written01-1998Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated04-2013Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Citation

This paper should be referenced as such :
Huret, JL
t(6;9)(p23;q34) DEK/NUP214
Atlas Genet Cytogenet Oncol Haematol. 2013;17(11):766-769.
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. January 1998
URL : http://AtlasGeneticsOncology.org/Anomalies/t0609.html

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indexed on : Fri Jul 11 13:08:59 CEST 2014


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