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

Written2016-11Henrik Hasle, Julie Damgaard Sandahl
Department of Pediatrics, Aarhus University Hospital, Skejby, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark; hasle@dadlnet.dk, Julie.damgaard@gmail.com

Abstract Review on t(6;9)(p22;q34) DEK/NUP214 in Childhood, with data on clinics, and the genes involved.

Keywords DEK; NUP214; Childhood; acute myeloid leukemia; myelodysplastic syndrome

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9865/3 AML with t(6;9)(p23;q34); DEK-NUP214v AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2);RPN1-EVI1
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
Atlas_Id 1359

Clinics and Pathology

Disease Acute myeloid leukemias 1238 (AML) and myelodysplastic syndromes (MDS)
Phenotype / cell stem origin t(6;9)(p22;q34) is a rare subtype of pediatric AML earlier only described in small series and case reports (Gupta, et al 2010, Ishiyama, et al 2012, Slovak, et al 2006). Two large studies both published in 2014 described the clinical, morphologic, and genetic characteristics: the I-BFM-study including 62 children of which 54 was diagnosed as AML and 8 as MDS, and the COG study investigating 48 children all diagnosed as AML (Sandahl, et al 2014, Tarlock, et al 2014). This review is based upon the 110 children from these two series.
There are no pediatric studies of stem cell origin. AML in children with t(6;9) is associated with French-American-British (FAB) type M2 (44%) and FAB type M4 (25%) (Sandahl, et al 2014, Tarlock, et al 2014).
Epidemiology The t(6;9)(p22;q34) was first described in a pediatric patient in 1982 (Kaneko, et al 1982). It is rare, found in only about 1% of all pediatric AML (Sandahl, et al 2014, Slovak, et al 2006, Tarlock, et al 2014) and associated with late onset with a median age 11 years and no patients below 2 years of age (Sandahl, et al 2014, Tarlock, et al 2014). There is an equal sex distribution with 53% males.
Cytology Basophilia is common in adults with t(6;9). In the I-BFM study, peripheral blood smears from 11 children and bone marrow smears from 15 children with t(6;9)(p22;q34) were evaluable for central review (Sandahl, et al 2014). All had mild to moderate bilinear dysplasia. Basophils were present in five patients (33%), four of which had 2% basophils, one patient (6%) had 1% basophils, none had > 2%. From the remaining 47 AML patients, reports on basophils were available in 16 cases; four patients had 1-2% basophils in BM smears, one had 0.4%, and no basophils were reported in the remaining 11. No Auer rods were seen in this reviewed pediatric series. Pseudo-Pelger cells were found in all reviewed material. Furthermore, almost all had tadpole blasts and many have bilobar blasts, both characteristic of AML-M3. However no patients were classified as FAB M3.
 
BM biopsies from pediatric t(6;9) AML illustrating morphologic characteristics A Pseudo-Pelger-Hüet anomaly tadpole blasts. Illustration from central review by Gitte Kerndrup (2013)
Treatment It has been suggested that Hematopoietic stem cell transplantation (HSCT) in first complete remission may improve outcome. In the I-BFM-study, the 5-year event-free survival was improved among patients treated the HSCT in CR1 compared with chemotherapy alone (68% vs. 18%; P<0.01) but it did not effect the OS (68% vs. 54%; P=0.48). In the COG study those who received HSCT in CR1 or CR2 had a survival of 60% vs. 21% in those treated with chemotherapy alone (Tarlock, et al 2014).
Prognosis Complete remission rate is significantly lower compared with pediatric AML patients without t(6;9)(Tarlock, et al 2014), but reported CR rates varied between 67 and 93%. (Sandahl, et al 2014, Tarlock, et al 2014) Furthermore, t(6;9) was associated with high risk of relapse 57%-64%, low 5-year EFS of 32% and 5-year OS around 45%(Sandahl, et al 2014, Tarlock, et al 2014).
The outcome seems better among pediatric t(6,9) patients compared with adults (Slovak, et al 2006).(Ishiyama, et al 2012, Slovak, et al 2006).
Among t(6;9) patients FLT3-ITD had a non-significant negative influence on survival with a 5-year overall survival compared with non-FLT3-ITD (22% versus 62%; p=0.13) in the I-BFM study (Sandahl, et al 2014). The OS in the COG study was in contrast higher with FLT3-ITD than without (40% vs. 27%; p>0.9) which may be explained by FLT3-ITD being allocated to hematopoietic stem cell transplantation (HSCT) (Sandahl, et al 2014, Tarlock, et al 2014)

Genetics

The t(6;9) is often associated with FLT3-ITD reported in 42% to 69% (Sandahl, et al 2014, Slovak, et al 2006, Tarlock, et al 2014).
In the I-BFM study, the gene expression profile was analyzed in 297 pediatric AML patients including eight t(6;9) AML cases. The t(6,9) cases had a significant signature with high expression levels of HOXA and the HOXB (HOXB2, (HOXB3, (HOXB4, HOXB5, HOXB6, HOXB8, and HOXB9) genes described previously (Hollink, et al 2011) but also with high expression of HIST2H4A, PRDM2 (RIZ), SESN1, and EYA3 (Sandahl, et al 2014).

Cytogenetics

Cytogenetics Morphological The translocation is easily detected by conventional karyotyping, only 4/62 pediatric cases were discovered solely by FISH or PCR (Sandahl, et al 2014).
Additional anomalies t(6;9)(p22;q34) often presents as the sole cytogenetic abnormality (81%). (Gupta, et al 2010). Additional abnormalities are described in 12-19%. (Sandahl, et al 2014) Recurrent aberrations in addition to t(6;9) have been described in 19% with loss of chromosome Y in three boys and trisomy 8 and trisomy 13 each present in three cases, either alone or combined (Sandahl, et al 2014).

Genes involved and Proteins

Gene NameDEK (DEK proto-oncogene)
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 NameNUP214 (nucleoporin 214kDa)
Location 9q34.13
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.
  

Bibliography

The t(6;9)(p22;q34) in myeloid neoplasms: a retrospective study of 16 cases
Gupta M, Ashok Kumar J, Sitaram U, Neeraj S, Nancy A, Balasubramanian P, Abraham A, Mathews V, Viswabandya  A, George B, Chandy M, Srivastava A, Srivastava VM
  Cancer Genet Cytogenet  2010 Dec;203(2):297-302
PMID 21156248
 
NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia  with a distinct HOX gene  expression pattern
Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Pratcorona M, Abbas S, Kuipers JE, van Galen JF,  Beverloo HB, Sonneveld E, Kaspers GJ, Trka J, Baruchel A, Zimmermann M, Creutzig U, Reinhardt D, Pieters R, Valk PJ, Zwaan CM
REFERENCE Blood  2011 Sep 29;118(13):3645-56
PMID 21813447
 
Prognostic factors for acute myeloid leukemia patients with t(6;9)(p23;q34) who underwent an allogeneic  hem atopoietic stem cell transplant
Ishiyama K, Takami A, Kanda Y, Nakao S, Hidaka M, Maeda T, Naoe T, Taniguchi S, Kawa K, Nagamura T, Tabuchi  K, Atsuta Y, Sakamaki H
Leukemia  2012 Jun;26(6):1416-9
PMID 22157737
 
Chromosome pattern in  childhood acute nonlymphocytic leukemia (ANLL)
Kaneko Y, Rowley JD, Maurer HS, Variakojis D, Moohr JW
Blood  1982 Aug;60(2):389-99
PMID 6953984
 
t(6;9)(p22;q34)/DEK-NUP214-rearranged pediatric myeloid leukemia: an international study of 62 patients
Sandahl JD, Coenen EA, Forestier E, Harbott J, Johansson B, Kerndrup G, Adachi S, Auvrignon A, Beverloo HB,  Cayuela JM, Chilton L, Fornerod M, de Haas V, Harrison CJ, Inaba H, Kaspers GJ, Liang DC, Locatelli F, Masetti R,  Perot C, Raimondi SC, Reinhardt K, Tomizawa D, von Neuhoff N, Zecca M, Zwaan CM, van den Heuvel-Eibrink MM, Hasle H
Haematologica  2014 May;99(5):865-72
PMID 24441146
 
A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multice nter 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
PMID 16628187
 
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is associated with poor outcome in childhood AML regardless of FLT3-ITD status: a report from the Children's Oncology Group
Tarlock K, Alonzo TA, Moraleda PP, Gerbing RB, Raimondi SC, Hirsch BA, Ravindranath Y, Lange B, Woods WG, Gamis AS, Meshinchi S
Br J  Haematol  2014 Jul;166(2):254-9
PMID 24661089
 

Citation

This paper should be referenced as such :
Hasle H, Sandahl JD
t(6;9)(p22;q34) DEK/NUP214 in Childhood;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0609p22q34ChildID1359.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(6;9)(p22;q34) DEK/NUP214

External links

Mitelman databaset(6;9)(p22;q34) [Case List]    t(6;9)(p22;q34) [Association List] Mitelman database (CGAP - NCBI)
arrayMapMorph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9865/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9989/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapMorph ( 9920/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
Disease databaset(6;9)(p22;q34) DEK/NUP214 in Childhood
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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