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

2013-03-01   Anwar N Mohamed  

1.Cytogenetics Laboratory, Pathology Department, Wayne State University School of Medicine, Detroit Medical Center, Detroit MI, USA

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 stem cell 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 (homeobox D13)
Location
2q31.1
Dna rna description
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 (homeobox D11)
Location
2q31.1
Dna rna description
See above.
Gene name
NUP98 (nucleoporin 98 kDa)
Location
11p15.4
Dna rna description
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.
Dna rna description
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

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.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.

Highly cited references

Pubmed IDYearTitleCitations
219482992011NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights.115
157558992005NUP98-HOXD13 transgenic mice develop a highly penetrant, severe myelodysplastic syndrome that progresses to acute leukemia.106
278891852016NUP98 Fusion Proteins Interact with the NSL and MLL1 Complexes to Drive Leukemogenesis.59
162823372006Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma.54
125438652003Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1.53
97666501998NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia.46
244147042014Age-related epigenetic drift in the pathogenesis of MDS and AML.44
223234522012Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model.41
266377872016Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome.40
286845282017Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/β-Catenin Activation.32
175455932007Retroviral insertional mutagenesis identifies genes that collaborate with NUP98-HOXD13 during leukemic transformation.32
185663222008Leukemic transformation in mice expressing a NUP98-HOXD13 transgene is accompanied by spontaneous mutations in Nras, Kras, and Cbl.30
187688192008Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell.28
159587032005Hox genes: from leukemia to hematopoietic stem cell expansion.26
183750362008Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.25
177124162007Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes.24
268470262016GFI1 as a novel prognostic and therapeutic factor for AML/MDS.23
168613512006The Flt3 receptor tyrosine kinase collaborates with NUP98-HOX fusions in acute myeloid leukemia.21
228556102012Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome.20
239580612014Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome.18
229272452012Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13-driven mouse model.18
186035482008Impaired differentiation and apoptosis of hematopoietic precursors in a mouse model of myelodysplastic syndrome.17
186480062008NUP98-HOX translocations lead to myelodysplastic syndrome in mice and men.17
198411792009A NUP98-HOXD13 fusion gene impairs differentiation of B and T lymphocytes and leads to expansion of thymocytes with partial TCRB gene rearrangement.15
157443442005Transplantable cell lines generated with NUP98-Hox fusion genes undergo leukemic progression by Meis1 independent of its binding to DNA.13
262024212015PKR inhibits the DNA damage response, and is associated with poor survival in AML and accelerated leukemia in NHD13 mice.12
174294292007Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets.11
117823542002The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).11
228855192012Gene expression profiling and candidate gene resequencing identifies pathways and mutations important for malignant transformation caused by leukemogenic fusion genes.10
231315832013Non-homologous end joining mediated DNA repair is impaired in the NUP98-HOXD13 mouse model for myelodysplastic syndrome.9
322026362020SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS.8
267424322016PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia.8
173775912007Mouse embryonic stem cells that express a NUP98-HOXD13 fusion protein are impaired in their ability to differentiate and can be complemented by BCR-ABL.8
307008382019The NUP98-HOXD13 fusion oncogene induces thymocyte self-renewal via Lmo2/Lyl1.6
293581802018Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS.6
244491682014Brief report: Loss of p15Ink4b accelerates development of myeloid neoplasms in Nup98-HoxD13 transgenic mice.6
293713262018Leptin-deficient obesity prolongs survival in a murine model of myelodysplastic syndrome.5
252205902014Progressive genomic instability in the Nup98-HoxD13 model of MDS correlates with loss of the PIG-A gene product.5
326521112020TLR2/6 signaling promotes the expansion of premalignant hematopoietic stem and progenitor cells in the NUP98-HOXD13 mouse model of MDS.4
317486062019Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.3
312034232019BOK promotes erythropoiesis in a mouse model of myelodysplastic syndrome.3
299284712018p300 suppresses leukemia development in NUP98-HOXD13 driven myelodysplastic syndrome.3
292286882017Altered follicular helper T cell impaired antibody production in a murine model of myelodysplastic syndromes.3
226134702012A NUP98-HOXD13 leukemic fusion gene leads to impaired class switch recombination and antibody production.3
109950092000Heterogenous 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.3
329983302020Evi1 Counteracts Anti-Leukemic and Stem Cell Inhibitory Effects of All-Trans Retinoic Acid on Flt3-ITD/Npm1c-Driven Acute Myeloid Leukemia Cells.2
316222812019A unique mutator phenotype reveals complementary oncogenic lesions leading to acute leukemia.2
311209982019HoxA9 binds and represses the Cebpa +8 kb enhancer.2
226063032012Depletion of cytotoxic T-cells does not protect NUP98-HOXD13 mice from myelodysplastic syndrome but reveals a modest tumor immunosurveillance effect.2
214942612011Backtracking to birth of the NUP98-HOXD13 gene fusion in an infant acute myeloid leukemia.2
350088352021Curcumin as an Epigenetic Therapeutic Agent in Myelodysplastic Syndromes (MDS).1
343212402021Mutant Idh2 Cooperates with a NUP98-HOXD13 Fusion to Induce Early Immature Thymocyte Precursor ALL.1
317238472019Attenuated Acceleration to Leukemia after Ezh2 Loss in Nup98-HoxD13 (NHD13) Myelodysplastic Syndrome.1
289539122017Myeloablative hematopoietic stem cell transplantation improves survival but is not curative in a pre-clinical model of myelodysplastic syndrome.1
176562572007A complex karyotype, including a three-way translocation generating a NUP98-HOXD13 transcript, in an infant with acute myeloid leukemia.1
347097392021Targeting miR-126 disrupts maintenance of myelodysplastic syndrome stem and progenitor cells.0
343597592021Cell-Extrinsic Differentiation Block Mediated by EphA3 in Pre-Leukaemic Thymus Contributes to Disease Progression.0
303463802018Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome.0
261170322015[Follicular Helper T Cells and Expression of PD-1 in Mice with Myelodysplastic Syndrome].0
226438312012FLT3 in lineage specification and plasticity.0
207399572010Meis1 disrupts the genomic imprint of Dlk1 in a NUP98-HOXD13 leukemia model.0
109310002000Generation of the NUP98-HOXD13 fusion transcript by a rare translocation, t(2;11)(q31;p15), in a case of infant leukaemia.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
109950092000Heterogenous 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 et al
214942612011Backtracking to birth of the NUP98-HOXD13 gene fusion in an infant acute myeloid leukemia.Emerenciano M et al
219482992011NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights.Gough SM et al
176562572007A complex karyotype, including a three-way translocation generating a NUP98-HOXD13 transcript, in an infant with acute myeloid leukemia.Hidaka E et al
153901872004Analysis of translocations that involve the NUP98 gene in patients with 11p15 chromosomal rearrangements.Kobzev YN et al
97666501998NUP98-HOXD13 gene fusion in therapy-related acute myelogenous leukemia.Raza-Egilmez SZ et al
117823542002The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15).Taketani T et al

Summary

Fusion gene

NUP98/HOXD13 NUP98 (11p15.4) HOXD13 (2q31.1) M t(2;11)(q31;p15)|NUP98/HOXD13 NUP98 (11p15.4) HOXD13 (2q31.1) TIC

Fusion gene

NUP98/HOXD13 NUP98 (11p15.4) HOXD13 (2q31.1) M t(2;11)(q31;p15)|NUP98/HOXD13 NUP98 (11p15.4) HOXD13 (2q31.1) TIC

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.
Atlas Image
Partial ideogram and G-banded karyotypes showing t(2;11)(q31;p15); arrows indicate breakpoints.

Citation

Anwar N Mohamed

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

Atlas Genet Cytogenet Oncol Haematol. 2013-03-01

Online version: http://atlasgeneticsoncology.org/haematological/1353/t(2;11)(q31;p15)