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t(11;12)(p15;q13) NUP98/HOXC11

t(11;12)(p15;q13) NUP98/HOXC13

Written2000-02Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2018-06Jean-Loup Huret
jean-loup.huret@atlasgeneticsoncology.org

Abstract Review on t(11;12)(p15;q13), with data on clinics, and the genes involved.

Keywords Chromosome 11; Chromosome 12; NUP98; HOXC11; HOXC13; Acute myeloid leukemia; Therapy-related myeloid neoplasms

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9873/3 AML without maturation
ICD-Morpho 9874/3 AML with maturation
ICD-Morpho 9867/3 Acute myelomonocytic leukaemia
ICD-Morpho 9891/3 Acute monoblastic and monocytic leukaemia
ICD-Morpho 9920/3 Therapy-related myeloid neoplasms
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1185
Note t(11;12)(p15;q13) with NUP98 and HOXC11 involvement has been described in 4 cases (Taketani et al., 2002; Gu et al., 2003), and with NUP98 and HOXC13 involvement in 3 additional cases (La Starza et al., 2003; Panagopoulos et al., 2003; Tosic et al., 2009).
 
  t(11;12)(p15;q13) G- banding - Courtesy Melanie Zenger and Claudia Haferlach.

Clinics and Pathology

Note To be noted that NUP98 gene was found rearranged but HOXC genes were not tested or neither NUP98 nor HOX genes were tested in 5 cases (Roulston et al., 1998; and Kobzev et al., 2004 are identical cases), all of which were treatment-related MDS or AML (t-MDS or t-AML): a 9 mths old boy, 3 female patients aged 39 yrs, 41 yrs and 55 yrs, and one other male patient (Roulston et al., 1998; Nishiyama et al., 1999; Wong et al., 1998; Masuya et al., 2002; Kobzev et al., 2004; Schmidt-Hieber et al., 2010). Previous diseases were Hodgkin's disease in 2 cases, AML and breast cancer in one case each.
As noted by La Starza et al., 2009, a NUP98-positive acute myeloid leukemia with a t(11;12)(p15;q13) can occur without HOXC cluster gene involvement.
Disease All the 7 cases with NUP98/HOXC hybrid gene were de novo acute myeloid leukemia: one AML without maturation (M1), four AML with maturation (M2), one acute myelomonocytic leukaemia (M4) and one acute monoblastic/monocytic leukaemia (M5b).
Epidemiology Sex ratio was 2M/2F in HOXC11 cases and 0M/3F in HOXC13 cases; more cases are needed to determine if this discrepancy is coincidental/stochastic. Patients were aged 14, 22, 40 and 41 yrs in HOXC11 cases and 47, 57, 59 yrs in HOXC13 cases
Prognosis Two cases were in complete remission (5 mths+, NA), and four cases were reported to have died (8 mths, 8mths, 19 mths, NA).

Cytogenetics

Cytogenetics Morphological The t(11;12)(p15;q13) was the sole abnormality in all the 7 cases with NUP98/HOXC hybrid gene ascertained. In the 5 cases of therapy-related leukemia without ascertainment of a NUP98/HOXC hybrid gene, the t(11;12)(p15;q13) was the sole abnormality in 2 cases, and additional abnormalities were found: a t(17;21)(q11;q22) with RUNX1 rearrangement in 1 case, a +21 in 1 case and a del(7q) and other abnormalities in 1 case.

Genes involved and Proteins

Gene NameNUP98 (nucleoporin 98 kDa)
Location 11p15.4
Dna / Rna alternate splicings
Protein 920 amino acids (aa) and other ioforms; NUP98 belongs to the nucleoporin gene family and encodes a 186 kDa precursor protein that undergoes autoproteolytic cleavage to produce a 98 kDa and 96 kDa nucleoporins. The 98 kDa nucleoporin contains a Gly-Leu-Phe-Gly (GLFG and FG) repeat in N-term, a GLEBS-like motif (which binds RAE1), and a RNA binding motif in C-term. NUP98 is involved in nuclear import/export, mitotic progression, and regulation of gene expression (Duheron and Fahrenkrog, 2015).
Gene NameHOXC11
Location 12q13.13; Starts at 53973126 and ends at 53976419 bp from pter ( according to hg38-Dec_2013)
 
Dna / Rna 915 nucleotids (nt), 2 exons
Protein 304 aa; the protein localizes in the nucleus; sequence-specific transcription factor which contains a homeodomain with helix-turn-helix (HTH) motif in aa 233 to 289.
Part of the Hox clusters. There is a timing mechanism to synchronize Hox gene expression during embryogenesis ("Hox clock"). HOX genes regulates the expression of genes that are implicated during embryogenesis (anterior-posterior patterning and limbs developments). HOX genes are also expressed in adult tissues (review in Deschamps and Duboule, 2017).
Gene NameHOXC13
Location 12q13.13; Starts at 53938792 and ends at 53946544 bp from pter ( according to hg19-Feb_2009) 
Note HOXC13 starts 37627 nt after the end of HOXC11.
Dna / Rna 993 nt, 2 exons
Protein 330 aa; the protein localizes in the nucleus; sequence-specific transcription factor which contains a homeodomain with helix-turn-helix (HTH) motif in aa 260 to 319.
Part of the Hox clusters. There is a timing mechanism to synchronize Hox gene expression during embryogenesis ("Hox clock"). HOX genes regulates the expression of genes that are implicated during embryogenesis (anterior-posterior patterning and limbs developments). HOX genes are also expressed in adult tissues (review in Deschamps and Duboule, 2017).

Result of the chromosomal anomaly

Hybrid gene
Description The NUP98 breakpoint was between exon 11 and 12 in three HOXC11 cases (Gu et al., 2003), and between exon 14 and 15 in the other HOXC11 case (Taketani et al., 2002). It was found between exon 15 and 16 in two HOXC13 cases (La Starza et al., 2003; Panagopoulos et al., 2003). The HOXC11 breakpoint was between exon 1 and 2 (Gu et al., 2003), or in exon 1 (Taketani et al., 2002). The HOXC13 breakpoint was between exon 1 and 2 (La Starza et al., 2003; Panagopoulos et al., 2003).
  
Fusion Protein
 
Description fuses the N-term NUP98 to the C-term of HOXC11 or HOXC13. This correspond to 469 aa or 628 aa from NUP98 in the HOXC11 cases and 715 aa in the HOXC13 cases fused to 77 aa from HOX11 (Gu et al., 2003), or 120 aa from HOX13 (Taketani et al., 2002).
  

Bibliography

Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock
Deschamps J, Duboule D
Genes Dev 2017 Jul 15;31(14):1406-1416
PMID 28860158
 
The nuclear pore complex: structure and function
Duheron V, Fahrenkrog B.
Atlas Genet Cytogenet Oncol Haematol. 2015;19(5):355-375. http://AtlasGeneticsOncology.org/Deep/NuclearPoreFunctionID20139.htm
 
Major form of NUP98/HOXC11 fusion in adult AML with t(11;12)(p15;q13) translocation exhibits aberrant trans-regulatory activity
Gu BW, Wang Q, Wang JM, Xue YQ, Fang J, Wong KF, Chen B, Shi ZZ, Shi JY, Bai XT, Wu DH, Chen Z, Chen SJ
Leukemia 2003 Sep;17(9):1858-64
PMID 12970787
 
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
 
A NUP98-positive acute myeloid leukemia with a t(11;12)(p15;q13) without HOXC cluster gene involvement
La Starza R, Brandimarte L, Pierini V, Nofrini V, Gorello P, Crescenzi B, Berchicci L, Matteucci C, Romoli S, Beacci D, Rosati R, Martelli MF, Mecucci C
Cancer Genet Cytogenet 2009 Sep;193(2):109-11
PMID 19665072
 
Two independent clones in myelodysplastic syndrome following treatment of acute myeloid leukemia
Masuya M, Katayama N, Inagaki K, Miwa H, Hoshino N, Miyashita H, Suzuki H, Araki H, Mitani H, Nishii K, Kageyama S, Minami N, Shiku H
Int J Hematol 2002 Feb;75(2):182-6
PMID 11939266
 
11p15 translocations involving the NUP98 gene in childhood therapy-related acute myeloid leukemia/myelodysplastic syndrome
Nishiyama M, Arai Y, Tsunematsu Y, Kobayashi H, Asami K, Yabe M, Kato S, Oda M, Eguchi H, Ohki M, Kaneko Y
Genes Chromosomes Cancer 1999 Nov;26(3):215-20
PMID 10502319
 
Fusion of the NUP98 gene and the homeobox gene HOXC13 in acute myeloid leukemia with t(11;12)(p15;q13)
Panagopoulos I, Isaksson M, Billström R, Strömbeck B, Mitelman F, Johansson B
Genes Chromosomes Cancer 2003 Jan;36(1):107-12
PMID 12461755
 
CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy
Roulston D, Espinosa R 3rd, Nucifora G, Larson RA, Le Beau MM, Rowley JD
Blood 1998 Oct 15;92(8):2879-85
PMID 9763573
 
Cytogenetic studies in acute leukemia patients relapsing after allogeneic stem cell transplantation
Schmidt-Hieber M, Blau IW, Richter G, Türkmen S, Bommer C, Thiel G, Neitzel H, Stroux A, Uharek L, Thiel E, Blau O
Cancer Genet Cytogenet 2010 Apr 15;198(2):135-43
PMID 20362228
 
Novel NUP98-HOXC11 fusion gene resulted from a chromosomal break within exon 1 of HOXC11 in acute myeloid leukemia with t(11;12)(p15;q13)
Taketani T, Taki T, Shibuya N, Kikuchi A, Hanada R, Hayashi Y
Cancer Res 2002 Aug 15;62(16):4571-4
PMID 12183408
 
Acute myeloid leukemia with NUP98-HOXC13 fusion and FLT3 internal tandem duplication mutation: case report and literature review
Tosić N, Stojiljković M, Colović N, Colović M, Pavlović S
Cancer Genet Cytogenet 2009 Sep;193(2):98-103
PMID 19665070
 
De novo AML with trilineage myelodysplasia and a novel t(11;12)(p15;q13)
Wong KF, Kwong YL, So CC
Cancer Genet Cytogenet 1998 Jan 1;100(1):49-51
PMID 9406580
 

Citation

This paper should be referenced as such :
Huret JL
t(11;12)(p15;q13) NUP98/HOXC11; t(11;12)(p15;q13) NUP98/HOXC13;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t1112ID1185.html
History of this paper:
Huret, JL. t(11;12)(p15;q13). Atlas Genet Cytogenet Oncol Haematol. 2000;4(1):33-34.
http://documents.irevues.inist.fr/bitstream/handle/2042/37595/02-2000-t1112ID1185.pdf


Translocations implicated (Data extracted from papers in the Atlas)

 t(11;12)(p15;q13) NUP98/HOXC11
 t(11;12)(p15;q13) NUP98/HOXC13

External links

Mitelman databaset(11;12)(p15;q13) [Case List]    t(11;12)(p15;q13) [Transloc-MCList] NUP98/HOXC11 [Fusion-MCList]
Mitelman databaset(11;12)(p15;q13) [Case List]    t(11;12)(p15;q13) [Transloc-MCList] NUP98/HOXC13 [Fusion-MCList]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9873/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9874/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9867/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9891/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9920/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
REVIEW articlesautomatic search in PubMed
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