title: NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern.
abstract: Translocations involving nucleoporin 98kD (NUP98) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML) but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically normal (CN)-AML cases. To determine their exact frequency, we screened > 1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1-specific RT-PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1-positive AML cases had significantly higher white blood cell counts (median, 147 × 10⁹/L), more frequent FAB-M4/M5 morphology (in 63%), and more CN-AML (in 78%), FLT3/internal tandem duplication (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1-negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was < 10% for both pediatric and adult NUP98/NSD1-positive AML patients. NUP98/NSD1-positive AML showed a characteristic HOX-gene expression pattern, distinct from, for example, MLL-rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed.
authors.affiliation: Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Iris H I M
authors.initials: IH
authors.lastname: Hollink
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: Susan T C J M
authors.initials: ST
authors.lastname: Arentsen-Peters
authors.forename: Marta
authors.initials: M
authors.lastname: Pratcorona
authors.forename: Saman
authors.initials: S
authors.lastname: Abbas
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Kuipers
authors.forename: Janneke F
authors.initials: JF
authors.lastname: van Galen
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.forename: Gert-Jan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.forename: Andre
authors.initials: A
authors.lastname: Baruchel
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005801:Genes, Homeobox; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011379:Prognosis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C465451:Nup98 protein, human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human