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

Disease

Acute megakaryoblastic leukemia (AML -M7)

Note

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).

Epidemiology

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).

Clinics

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).

Prognosis

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)
Location
11p15.4
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))
Location
12p13.33
Note
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

Description

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

Transcript

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).

Description

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.

Oncogenesis

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

Article Bibliography

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

Summary

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

Citation

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/css/lib/img/humanGenome

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