title: NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern.
abstract: Cytogenetic abnormalities and early response to treatment are the main prognostic factors in acute myeloid leukemia (AML). Recently, NUP98/NSD1 (t(5; 11)(q35; p15)), a cytogenetically cryptic fusion, was described as recurrent event in AML, characterized by dismal prognosis and HOXA/B gene overexpression. Using split-signal fluorescence in situ hybridization, other NUP98-rearranged pediatric AML cases were identified, including several acute megakaryoblastic leukemia (AMKL) cases with a cytogenetically cryptic fusion of NUP98 to JARID1A (t(11;15)(p15;q35)). In this study we screened 105 pediatric AMKL cases to analyze the frequency of NUP98/JARID1A and other recurrent genetic abnormalities. NUP98/JARID1A was identified in 11/105 patients (10.5%). Other abnormalities consisted of RBM15/MKL1 (n=16), CBFA2T3/GLIS2 (n=13) and MLL-rearrangements (n=13). Comparing NUP98/JARID1A-positive patients with other pediatric AMKL patients, no significant differences in sex, age and white blood cell count were found. NUP98/JARID1A was not an independent prognostic factor for 5-year overall (probability of overall survival (pOS)) or event-free survival (probability of event-free survival (pEFS)), although the 5-year pOS for the entire AMKL cohort was poor (42 ± 6%). Cases with RBM15/MLK1 fared significantly better in terms of pOS and pEFS, although this was not independent from other risk factors in multivariate analysis. NUP98/JARID1A cases were characterized by HOXA/B gene overexpression, which is a potential druggable pathway. In conclusion, NUP98/JARID1A is a novel recurrent genetic abnormality in pediatric AMKL.
authors.affiliation: Department of Pediatric Hematology/Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: J D E
authors.initials: JD
authors.lastname: de Rooij
authors.forename: I H I M
authors.initials: IH
authors.lastname: Hollink
authors.forename: S T C J M
authors.initials: ST
authors.lastname: Arentsen-Peters
authors.forename: J F
authors.initials: JF
authors.lastname: van Galen
authors.forename: H
authors.initials: H
authors.lastname: Berna Beverloo
authors.forename: A
authors.initials: A
authors.lastname: Baruchel
authors.forename: J
authors.initials: J
authors.lastname: Trka
authors.forename: D
authors.initials: D
authors.lastname: Reinhardt
authors.forename: E
authors.initials: E
authors.lastname: Sonneveld
authors.forename: M
authors.initials: M
authors.lastname: Zimmermann
authors.forename: T A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: R
authors.initials: R
authors.lastname: Pieters
authors.forename: S
authors.initials: S
authors.lastname: Meshinchi
authors.forename: M M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D002895:Chromosomes, Human, Pair 5; D005260:Female; D020869:Gene Expression Profiling; D005801:Genes, Homeobox; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D056485:Retinoblastoma-Binding Protein 2 / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2