t(11;12)(p15;p13) NUP98/KDM5A

2013-01-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
2.Department of Clinical Genetics, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

Clinics and Pathology


Acute megakaryoblastic leukemia (AMKL) was so far divided into three subgroups: AMKL arising in patients with Down syndrome (DS-AMKL), AMKL with a t(1;22)(p13;q13) giving rise of a 5 OTT - 3 MAL fusion gene, and "other" AMLKs, non Down syndrome / non t(1;22).
Two new categories have recently been individualized from the subgroup "non Down syndrome / non t(1;22)": the inv(16)(p13q24) CBFA2T3/GLIS2, and the t(11;12)(p15;p13) NUP98/KDM5A (Gruber et al., 2012; Thiollier et al., 2012). This t(11;12)(p15;p13) has been described earlier in a single case (van Zutven et al., 2006).


From the two recent studies, t(11;12)(p15;p13) NUP98/KDM5A was found in about 10% of pediatric acute megakaryoblastic leukemia, excluding AMLKs occuring in Down syndrome patients; NUP98/KDM5A was detected in 8% (4 of 48) of pediatric cases. This chimeric transcript was not detected in adult AMKLs (Gruber et al., 2012). From another validation cohort of 22 non-DS pediatric AMKL, 9 DS AMKL, and 8 adult AMKL, a NUP98/KDM5A fusion was characterized in two patients (Thiollier et al., 2012).


7 cases to date; data on age and sex are available in 5 cases (van Zutven et al., 2006; Gruber et al., 2012): there was 5 boys and no girl; sex ratio, so far, appears to be highly unbalanced, although the sample is very small; median age was 1 year 4 months (range: 1 year - 4 years).


Prognostic data available in only one case (van Zutven et al., 2006) : the patient remained in complete remission for at least 5 years.

Genes Involved and Proteins

Gene name
NUP98 (nucleoporin 98 kDa)
Protein description
920 amino acids; 97 kDa; contains repeated motifs (GLFG and FG) in N-term and a RNA binding motif in C-term. Nucleoporin: associated with the nuclear pore complex; role in nucleocytoplasmic transport processes.
Gene name
KDM5A (Jumonji, AT rich interactive domain 1A (RBBP2-like))
The gene was previously known as JARID1A.
Protein description
1722 amino acids; 196 kD; retinoblastoma binding protein 2. Lysine-specific histone 3 demethylase; involved in chromatin-regulation; can function as a transcriptional repressor. KDM5A-mediated histone H3 lysine 4 demethylation contributes to silencing of retinoblastoma target genes (Chicas et al., 2012). Dysregulation of KDM5A is associated with various human cancers: gastric cancer, lung cancer, breast cancer (Hou et al., 2012).

Result of the Chromosomal Anomaly


In-frame fusion of the first 13 exons of NUP98 to exons 28-31 of KDM5A.


5 NUP98 - 3 KDM5A.

Detection protocole

FISH: BAC clones RP11-348A20 (NUP98) and RP11-283I3 (spanning KDM5A exon 11-31) colocalize.
Atlas Image
Schematic representation of the fusion NUP98-KDM5A (previously named NUP98-JARID1A). From up to down: NUP98, JARID1A and the putative chimeric NUP98-JARID1A structure. FG-repeats: phenylalanine-glycine repeats; JMJ: Jumonji domains; ARID: AT-rich interaction domain; PHD: plant homeodomain fingers or LAP domains. The arrow indicates the position of the fusion (Laura JCM van Zutven and H Berna Beverloo).


The NUP98/KDM5A fusion protein contains the Phe-Gly (FG) repeats of the N-terminal part of NUP98. The KDM5A (JARID1A) sequence starting with exon 28 still contains the sequence encoding the C-terminal PHD domain.


Results in deregulation of HOXA genes through recruitment of the histone acetyltransferase CBP/p300 (Thiollier et al., 2012).

Highly cited references

Pubmed IDYearTitleCitations
281127372017Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.61
271144622016Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study.33
280631902017Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome.18
316984612019Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities.11
323815792021The clinical and biological characteristics of NUP98-KDM5A in pediatric acute myeloid leukemia.10
316124662020Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup.10
335124582021Modeling and targeting of erythroleukemia by hematopoietic genome editing.9
349036202022Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation.7
294275262018NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.7
326207642020Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.5
338329212021Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.1
357215022022Generation of a H9 Clonal Cell Line With Inducible Expression of NUP98-KDM5A Fusion Gene in the AAVS1 Safe Harbor Locus.0
308423872019[Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia].0


Pubmed IDLast YearTitleAuthors
226153822012H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence.Chicas A et al
231535402012An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia.Gruber TA et al
229372032012Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer.Hou J et al
230456052012Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.Thiollier C et al
164190552006Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene.van Zutven LJ et al


Fusion gene

NUP98/KDM5A NUP98 (11p15.4) KDM5A (12p13.33) M t(11;12)(p15;p13) t(11;21;12)(p15;p13;p13)|NUP98/KDM5A NUP98 (11p15.4) KDM5A (12p13.33) TIC


Jean-Loup Huret

t(11;12)(p15;p13) NUP98/KDM5A

Atlas Genet Cytogenet Oncol Haematol. 2013-01-01

Online version: http://atlasgeneticsoncology.org/haematological/1428/t(11;12)(p15;p13)

Historical Card

2006-04-01 t(11;12)(p15;p13) NUP98/KDM5A by  H Berna Beverloo,Laura JCM van Zutven 

Department of Clinical Genetics, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands