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Acute Leukemias

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.

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Correspondence to C Michel Zwaan.

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JDEdR, IHIMH, RP, MMvdH-E and CMZ designed the study. AB, JT, DR, ES, TAA and SM made this research possible by collecting patient samples and clinical data. JDEdR, IHIMH, STCJMA-P and JFvG performed the laboratory research. JDEdR, IHIMH, HBB, MMvdH-E and CMZ analyzed and interpreted the data. MZ performed statistical analysis. JDEdR, MMvdH-E and CMZ wrote the manuscript. All authors critically reviewed the manuscript and gave their final approval.

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de Rooij, J., Hollink, I., Arentsen-Peters, S. et al. NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia 27, 2280–2288 (2013). https://doi.org/10.1038/leu.2013.87

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