t(11;12)(p15;p13) NUP98/KDM5A
2013-01-01 Jean-Loup Huret Affiliation1.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
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).
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.
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.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 39974131 | 2025 | Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia. | 99 |
| 34903620 | 2022 | Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation. | 56 |
| 31698461 | 2019 | Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities. | 51 |
| 37301844 | 2023 | The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation. | 46 |
| 36815378 | 2023 | Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia. | 44 |
| 39359452 | 2024 | Prognostic importance of NUP98-rearrangements in acute myeloid leukemia: A systematic review and meta-analysis. | 44 |
| 28112737 | 2017 | Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. | 41 |
| 27114462 | 2016 | Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study. | 39 |
| 33512458 | 2021 | Modeling and targeting of erythroleukemia by hematopoietic genome editing. | 38 |
| 32620764 | 2020 | Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion. | 36 |
| 33832921 | 2021 | Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies. | 24 |
| 35721502 | 2022 | Generation of a H9 Clonal Cell Line With Inducible Expression of NUP98-KDM5A Fusion Gene in the AAVS1 Safe Harbor Locus. | 14 |
| 32381579 | 2021 | The clinical and biological characteristics of NUP98-KDM5A in pediatric acute myeloid leukemia. | 13 |
| 38302680 | 2024 | ''Cannibalistic'' phagocytosis in acute megakaryoblastic leukemia with NUP98::KDM5A fusion. | 0 |
| 28063190 | 2017 | Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. | 0 |
| 29427526 | 2018 | NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy. | 0 |
| 31612466 | 2020 | Patients aged less than 3 years with acute myeloid leukaemia characterize a molecularly and clinically distinct subgroup. | 0 |
| 30842387 | 2019 | [Prognostic significance of chimeric fusion gene analysis in pediatric acute megakaryoblastic leukemia]. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 22615382 | 2012 | H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. | Chicas A et al |
| 23153540 | 2012 | An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. | Gruber TA et al |
| 22937203 | 2012 | Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. | Hou J et al |
| 23045605 | 2012 | Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. | Thiollier C et al |
| 16419055 | 2006 | Identification 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
Historical Card
2006-04-01 t(11;12)(p15;p13) NUP98/KDM5A by H Berna Beverloo,Laura JCM van Zutven Affiliation
Department of Clinical Genetics, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands
