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t(2;11)(q31;p15) NUP98/HOXD13

t(2;11)(q31;p15) NUP98/HOXD11

Written2013-03Anwar N Mohamed
Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
ICD-Morpho 9989/3 Myelodysplastic syndrome, unclassifiable
Atlas_Id 1353
Note t(2;11)(q31;p15) is an example of a variant translocation involving NUP98 gene at 11p15 which is fused with HOXD13 gene at 2q31. This fusion produces a chimeric protein with leukemogenic activity. t(2;11)(q31;p15) is associated with myeloid malignancies.
 
  Partial ideogram and G-banded karyotypes showing t(2;11)(q31;p15); arrows indicate breakpoints.

Clinics and Pathology

Disease t(2;11)(q31;p15) is a rare but nonrandom translocation, reported in de novo acute myeloid leukemia (AML) as well as therapy related myelodysplastic syndrome/therapy related acute myeloid leukemia (t-MDS/t-AML), and one case of chronic myeloid leukemia in blast crisis (CML-BC).
Phenotype / cell stem origin Mostly AML-M4; bone marrow displaying monocytic features; AML-M6 in one case.
Epidemiology Generally the incidence of NUP98 rearrangements in leukemia is difficult to estimate probably 1-2% of AML cases. The t(2;15)(q32;p15) is rare; around 8 cases in literature; reported in male and female with 1:1 ratio; Infants under the age of a year; children (10-15 years) as well as adults (59-62 years); over-representation in Asian race in particular Japanese.
It has been shown that NUP98/11p15 is a frequent target for chromosomal rearrangements following chemotherapies with DNA topoisomerase II inhibitors. Interestingly, there are at least three infants leukemia with NUP98-HOXD13 gene fusion. It has been suggested that a high intake of certain diets rich in flavonoids during pregnancy increases the risk of infant leukemia due to the inhibition effect on topo II activity. It is worth to mention that in one infant, the NUP98-HOXD13 gene fusion was demonstrated retrospectively in neonatal blood spot. This provides strong evidence that the fusion is a prenatal event.
Clinics Peripheral blood; High white cell counts (WBC) with elevated monocytes; low platelets;
Bone Marrow: Hypercellular marrow with monocytic differentiation;
Immunophenotypes; Cell surface marker expression included CD13, CD14, CD33, CD34, HLA-DR, CD11b, CD65.
Prognosis Due to rarity of t(2;11) leukemia, it is difficult to determine the prognostic significance of this translocation in leukemia. However, all de novo t(2;11) AML achieved remission, while patients with t-AML progressed rapidly. Generally, NUP98 gene fusion in leukemia predicts poor clinical outcome.

Cytogenetics

Cytogenetics Morphological Sole Anomaly; t(2;11)(q31;p15) was a sole anomaly in 5/8 cases.
Additional anomalies Trisomy 8 in one case; balanced translocations in one case; in a CML-BC case t(2;11)(q31;p15) was secondary to Ph chromosome.
Variants t(2;11;9)(q31;p15;q22)/NUP98-HOXD13 fusion in one case.

Genes involved and Proteins

Gene Name HOXD13
Location 2q31.1
Dna / Rna HOXD11 and HOXD13 genes, located on chromosome 2q31, are member of a large family of developmental homeobox genes. Homeobox genes encode evolutionarily conserved transcription factors that appear to be involved in body plan formation and embryonic development, and also play a critical role in limb development.
Gene Name HOXD11
Location 2q31.1
Dna / Rna See above.
Gene Name NUP98
Location 11p15
Dna / Rna NUP98 gene, located on chromosome 11p15, encodes a 98-KD protein a component of nuclear pore complex (NPC). NUP98 is found in the nucleoplasmic and cytoplasmic domains of the NPC, and functions as a transport co-factor of RNA and protein between the nucleus and cytoplasm. In addition, NUP98 appear to be involved in mitotic spindle formation and in cell cycle progression. Haploinsufficiency of NUP98 gene has been shown to cause premature separation of sister chromatids leading to sever aneuploidy.
In leukemia, there are at least 29 different partner genes fused with NUP98, 50% of which are homeobox genes. Different genes are likely associated with different leukemic phenotypes.

Result of the chromosomal anomaly

Hybrid gene
Description 5'-NUP98-HOXD13-3' fusion is the oncogeneic product of the t(2;11); exon 12 of NUP98 gene is fused in-frame with exon 2 of HOXD13 gene.
  
Fusion Protein
Description NUP98 fusion gene encodes a chimeric protein which is the amino terminal portion of NUP98 protein fuses the carboxyl portion of the partner gene HOXD13. The fused protein acts as an aberrant transcription factor. Several studies have demonstrated that NUP98-HOXD13 fusion protein blocks differentiation of hematopoietic precursor cells, and has aberrant self-renewal capacity.
  

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.

Bibliography

Heterogenous fusion transcripts involving the NUP98 gene and HOXD13 gene activation in a case of acute myeloid leukemia with the t(2;11)(q31;p15) translocation.
Arai Y, Kyo T, Miwa H, Arai K, Kamada N, Kita K, Ohki M.
Leukemia. 2000 Sep;14(9):1621-9.
PMID 10995009
 
Backtracking to birth of the NUP98-HOXD13 gene fusion in an infant acute myeloid leukemia.
Emerenciano M, Meyer C, Macedo-Silva ML, de Meis E, Dobbin JA, Marschalek R, Pombo-de-Oliveira MS.
Leukemia. 2011 Jul;25(7):1192-4. doi: 10.1038/leu.2011.51. Epub 2011 Apr 15.
PMID 21494261
 
NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights.
Gough SM, Slape CI, Aplan PD.
Blood. 2011 Dec 8;118(24):6247-57. doi: 10.1182/blood-2011-07-328880. Epub 2011 Sep 26. (REVIEW)
PMID 21948299
 
A complex karyotype, including a three-way translocation generating a NUP98-HOXD13 transcript, in an infant with acute myeloid leukemia.
Hidaka E, Tanaka M, Matsuda K, Ishikawa-Matsumura M, Yamauchi K, Sano K, Honda T, Wakui K, Yanagisawa R, Nakazawa Y, Sakashita K, Shiohara M, Ishii E, Koike K.
Cancer Genet Cytogenet. 2007 Jul 15;176(2):137-43.
PMID 17656257
 
Analysis of translocations that involve the NUP98 gene in patients with 11p15 chromosomal rearrangements.
Kobzev YN, Martinez-Climent J, Lee S, Chen J, Rowley JD.
Genes Chromosomes Cancer. 2004 Dec;41(4):339-52.
PMID 15390187
 
NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia.
Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, Shows TB, Aplan PD.
Cancer Res. 1998 Oct 1;58(19):4269-73.
PMID 9766650
 
The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).
Taketani T, Taki T, Shibuya N, Ito E, Kitazawa J, Terui K, Hayashi Y.
Cancer Res. 2002 Jan 1;62(1):33-7.
PMID 11782354
 

Citation

This paper should be referenced as such :
Mohamed AN
t(2;11)(q31;p15) NUP98/HOXD13; t(2;11)(q31;p15) NUP98/HOXD11;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0211q31p15ID1353.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(2;11)(q31;p15) NUP98/HOXD13
 t(2;11)(q31;p15) NUP98/HOXD11

External links

NUP98 (11p15.4) HOXD13 (2q31.1)

NUP98 (11p15.4) HOXD13 (2q31.1)

NUP98 (11p15.4) HOXD13 (2q31.1)

NUP98 (11p15.4) HOXD13 (2q31.1)

Mitelman databaset(2;11)(q31;p15) [Case List]    t(2;11)(q31;p15) [Association List] Mitelman database (CGAP - NCBI)
Mitelman databaset(2;11)(q31;p15) [Case List]    t(2;11)(q31;p15) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9861/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9920/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9975/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMapTopo ( C42) Morph ( 9989/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databaseNUP98/HOXD13 [MCList]  NUP98 (11p15.4) HOXD13 (2q31.1)
TICdbNUP98/HOXD13  NUP98 (11p15.4) HOXD13 (2q31.1)
Mitelman databaseNUP98/HOXD13 [MCList]  NUP98 (11p15.4) HOXD13 (2q31.1)
TICdbNUP98/HOXD13  NUP98 (11p15.4) HOXD13 (2q31.1)
 
Disease databaset(2;11)(q31;p15) NUP98/HOXD13
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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