NUP98 is rearranged in 3.8% of pediatric AML forming a clinical and molecular homogenous group with a poor prognosis.
Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.|Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.
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Struski
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.
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Lagarde
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.
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Bories
Department of Pediatric Oncology, University Hospital of Toulouse, Toulouse, France.
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Puiseux
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.
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Prade
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, University Hospital of Saint-Louis, Paris, France.
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Cuccuini
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, Hospices Civils de Lyon, Lyon, France.
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Pages
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, University Hospital of Haut-Leveque, Bordeaux, France.
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Bidet
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, University Hospital of Hautepierre, Strasbourg, France.
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Gervais
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Medical Genetic, University Hospital of La Timone, Marseille, France.
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Lafage-Pochitaloff
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Medical Genetic, University Hospital Jeanne de Flandre, University of Lille 2, Lille, France.
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C
Roche-Lestienne
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Genetic, University Hospital Bretonneau, Tours, France.
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Barin
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Oncology Genetic, Cancer Institute Henri Becquerel, Rouen, France.
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Penther
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, University Hospital of Saint-Étienne, Saint-Etienne, France.
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Nadal
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Genetic, University Hospital Necker, Paris, France.
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I
Radford-Weiss
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Genetic, University Hospital Saint-Jacques, Besancon, France.
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MA
Collonge-Rame
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, University Hospital Robert Debré, Reims, France.
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B
Gaillard
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Cytogenetic, University Hospital of Dijon, Dijon, France.
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Mugneret
Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.|Department of Haematology, Oncology and Immunology, University Hospital of Grenoble, Grenoble, France.
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Lefebvre
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.
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Bart-Delabesse
Department of Pediatric Oncology, University Hospital of Trousseau, Paris, France.
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0000-0001-8363-1622
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Petit
Department of Pediatric Oncology, University Hospital of Trousseau, Paris, France.
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Leverger
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.
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Broccardo
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.|Groupe Francophone de Cytogénétique Hématologique (GFCH), Paris, France.
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Luquet
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.|Department of Pediatric Oncology, University Hospital of Toulouse, Toulouse, France.
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Pasquet
Department of Haematology, University Hospital of Toulouse, University of Toulouse, Centre of Research on Cancer of Toulouse (CRCT), Toulouse, France.
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Delabesse
D000483:Alleles; D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D044127:Epigenesis, Genetic; D059472:Exome; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008297:Male; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D015398:Signal Transduction; D014178:Translocation, Genetic; D025721:WT1 Proteins / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
D014408:Biomarkers, Tumor; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D025721:WT1 Proteins; C093350:nuclear pore complex protein 98; D051941:fms-Like Tyrosine Kinase 3