inv(11)(p15q23) NUP98/KMT2A

2017-02-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France.


Review on inv(11)(p15q23) NUP98/KMT2A with data on clinics and on the genes involved.

Clinics and Pathology


inv(11)(p15q23) has been found in myelodysplasia, acute myeloid leukemia, treatment related leukemia, acute lymphocytic leukemia, hairy cell leukemia, multiple myeloma, peripheral T-cell lymphoma.

Phenotype stem cell origin

There were 4 cases of myelodysplasia: a chronic myelomonocytic leukemia (CMMoL), a refractory anemia with excess blasts in transformation (RAEBt), and 2 myelodysplastic syndromes (MDS) not otherwise specified (NOS). (Bielorai et al., 2003; Harrison et al. et al., 1998; Inaba et al., 1988; Nebral et al., 2005).
There were 9 cases of acute myeloid leukemia: 2 cases of acute myeloblastic leukemia without maturation (FAB type M1), 3 cases of acute myeloblastic leukemia with maturation (FAB type M2), 1 case of acute promyelocytic leukaemia (AML- M3), 2 cases of acute myelomonocytic leukemia AML- M4), and 1 case of acute myeloid leukemia, NOS (Casas et al., 2003; Harrison et al., 1998; Kaltenbach et al., 2010; Larramendy et al., 2002; Nebral et al., 2005; Odero et al., 2001; Xu et al., 2001; Yan et al., 2001).
There were 4 cases of treatment related myeloid malignancy: 1 RAEBt after Hodgkin disease and a therapy-related RAEBt evolving toward AML-M5, and two FAB type M4 AML, one of which occurred after treatment of ALL. (Harrison et al., 1998; Nichols et al., 2002; Pui et al., 1989; Secker-Walker et al., 1998).
There was a case of childhood ALL (Heerema et al., 1992), a hairy cell leukemia (Haglund et al., 1994), a multiple myeloma (Sawyer et al., 2014), and a peripheral T-cell lymphoma (Lepretre et al., 2000).
The only 2 cases where NUP98/KMT2A fusion was ascertained were cases of M1 and M2 AMLs in a male patient aged 79 years and a female patient aged 30 years. Both patients died of disease. The inv(11)(p15q23) was the sole chromosome abnormality (Kaltenbach et al., 2010).


Myeloid malignancy cases were 8 male and 9 female patients, median age was 40-44 years, range 2-79 years, with 5 children cases. Lymphoid malignancy cases sex ratio and ages were: 1M/3F, 17 yrs, 40 yrs, 53 yrs.


Data on survival is too scarce.

Genes Involved and Proteins

As said above, there was no evidence of involvement of KMT2A (MLL) in 2 cases (Harrison et al., 1998), whereas there was an in-frame fusion transcript between NUP98 and KMT2A in 2 patients (Kaltenbach et al., 2010).
An hemizygous deletion of DDX10 and ATM was detected in one case (Nebral et al., 2005)
Gene name
NUP98 (nucleoporin 98 kDa)
Data from Mohamed, 2016: .
Dna rna description
NUP98 is one of several genes located in the imprinted gene domain of chromosome 11p15. Combined haploinsufficiency of NUP98 and RAE1 has been shown to result in premature separation of sister chromatids, leading to severe aneuploidy. NUP98 plays roles in gene expression, mitotic spindle formation, and cell cycle progression.
NUP98 gene is fused to a large number of "partner genes" caused primarily by balanced translocations and inversions which are associated with a wide variety of hematological malignancies including AML and MDS (de novo and therapy related), CML-blast crisis, and pre T- ALL. To date, no NUP98 fusion gene has been described in B-cell malignancies. At least 30 different partner genes are reported to fuse with NUP98; 50% of which are homeobox genes. Approximately 10% of patients with NUP98 fusions have T-ALL; most commonly, these malignancies are associated with NUP98-RAP1GDS1 gene fusions. This suggests that different partner genes are associated with different leukemia, although such associations are rarely exclusive. Although NUP98 breakpoints in these translocations are variable located between introns 9 to 14, a chimeric transcript consisting of the 5 portion of NUP98 fused in-frame to the 3 portion of the partner genes is generated in all.
Protein description
NUP98 gene encodes two alternatively spliced mRNA variants: NUP98 and NUP98-NUP96 that are cleaved to produce two distinct nucleoporins, NUP98 and NUP96. The NUP98 is a 98 kDa protein component of the nuclear pore complex (NPC) family which is involved in the trafficking of RNA and protein between the nucleus and cytoplasm. The NUP98 protein contains two partially characterized functional domains: a GLFG repeat region, which serves as a nuclear transport receptor docking surface, and a GLEBS domain, which mediates the interaction with the RAE1 mRNA nuclear export factor. Both domains are located within the N-terminal portion of NUP98. The chimeric NUP98 protein that results from translocations always retains the intact N-terminal GLFG repeats of NUP98 and the C-terminal domain of the partner protein. NUP96 is a scaffold component of the NPC (Mohamed, 2016).
Gene name
KMT2A (myeloid/lymphoid or mixed lineage leukemia)
Dna rna description
37 exons, spanning about 120 kb; 13-15 mRNA
Protein description
3969 amino acids, 431 kDa; Transcriptional regulatory factor. MLL is known to be associated with more than 30 proteins, including the core components of the SWI/SNF chromatin remodeling complex and the transcription complex TFIID. MLL binds promotors of HOX genes through acetylation and methylation of histones. MLL is a major regulator of hematopoesis and embryonic development, through regulation of HOX genes expression regulation (HOXA9 in particular).

Result of the Chromosomal Anomaly


in-frame fusion transcript between exon 13 of NUP98 and exon 2 of KMT2A (Kaltenbach et al., 2010).


Pubmed IDLast YearTitleAuthors
127486722003B-cell lymphoma developing in the donor 9 years after donor-origin acute myeloid leukemia post bone marrow transplantation.Bielorai B et al
145539422003Changes in apoptosis-related pathways in acute myelocytic leukemia.Casas S et al
81673431994Hairy cell leukemia is characterized by clonal chromosome abnormalities clustered to specific regions.Haglund U et al
95932861998Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants.Harrison CJ et al
15649541992Cytogenetic analysis in relapsed childhood acute lymphoblastic leukemia.Heerema NA et al
32937711988Childhood myelodysplastic syndromes with 11p15 translocation.Inaba T et al
205586182010NUP98-MLL fusion in human acute myeloblastic leukemia.Kaltenbach S et al
120319122002Overexpression of translocation-associated fusion genes of FGFRI, MYC, NPMI, and DEK, but absence of the translocations in acute myeloid leukemia. A microarray analysis.Larramendy ML et al
107008712000Chromosome abnormalities in peripheral T-cell lymphoma.Lepretre S et al
164081022006Combination of broad molecular screening and cytogenetic analysis for genetic risk assignment and diagnosis in patients with acute leukemia.Meyer-Monard S et al
159512872005Screening for NUP98 rearrangements in hematopoietic malignancies by fluorescence in situ hybridization.Nebral K et al
122006802002Therapy-related myelodysplastic syndrome after autologous stem cell transplantation for breast cancer.Nichols G et al
114559852001Further characterization of complex chromosomal rearrangements in myeloid malignancies: spectral karyotyping adds precision in defining abnormalities associated with poor prognosis.Odero MD et al
27874771989Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia.Pui CH et al
244975332014Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease.Sawyer JR et al
95932901998Secondary acute leukemia and myelodysplastic syndrome with 11q23 abnormalities. EU Concerted Action 11q23 Workshop.Secker-Walker LM et al
115160962001Molecular cytogenetic characterization and clinical relevance of additional, complex and/or variant chromosome abnormalities in acute promyelocytic leukemia.Xu L et al
112977652001Trisomy 8 and monosomy 7 detected in bone marrow using primed in situ labeling, fluorescence in situ hybridization, and conventional cytogenetic analyses. A study of 54 cases with hematological disorders.Yan J et al


Fusion gene



inv(11)(p15q23) is an heterogeneous disease, since a NUP98/KMT2A hybrid gene and fusion protein was detected in only 2 cases (Kaltenbach et al., 2010), whereas there was no evidence of involvement of KMT2A (MLL) in 2 other cases (Harrison et al., 1998). We herein review 21 cases of inv(11)(p15q23), most of them were not studied at the gene level. Was excluded in this review a case of precursor B-ALL where the inv(11)(p15q23) had instead a hidden MLL/ENL hybrid gene (Meyer-Monard et al., 2006). inv(11)(p15q23) has also been found in a case of breast adenocarcinoma, an adenocarcinoma of the ovary, a case of myxoid chondrosarcoma and a mesenchymal tumor, NOS of the corpus uteri, and are not herein reviewed (Mitelman database).


Jean-Loup Huret

inv(11)(p15q23) NUP98/KMT2A

Atlas Genet Cytogenet Oncol Haematol. 2017-02-01

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