NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern

• Published in: Leukemia Vol. 27; no. 12; pp. 2280 - 2288
• Main Authors: de Rooij, J D E, Hollink, I H I M, Arentsen-Peters, S T C J M, van Galen, J F, Berna Beverloo, H, Baruchel, A, Trka, J, Reinhardt, D, Sonneveld, E, Zimmermann, M, Alonzo, T A, Pieters, R, Meshinchi, S, van den Heuvel-Eibrink, M M, Zwaan, C Michel
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2013
• Subjects: Abnormalities; Acute myeloid leukemia; Adolescent; Base Sequence; Blood; Bone marrow; Child; Child, Preschool; Chromosomes; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 5; Cytogenetics; Down syndrome; Female; Fluorescence; Fluorescence in situ hybridization; Frequency analysis; Gene expression; Gene Expression Profiling; Gene mutations; Genes; Genes, Homeobox; Genetic abnormalities; Hematology; HOX gene; Humans; Identification and classification; Infant; Infant, Newborn; Kinases; Leukemia; Leukemia, Megakaryoblastic, Acute - genetics; Leukocytes; Male; Medical prognosis; Molecular Sequence Data; Multivariate analysis; Mutation; Nuclear Pore Complex Proteins - genetics; Oncology; Patients; Pediatrics; Retinoblastoma-Binding Protein 2 - genetics; Risk analysis; Risk factors; Survival; Translocation, Genetic; Czech Republic; Netherlands; United States > US; Hague Netherlands; Paris France; France; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.87

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.