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), C_BFA2T3/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

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INFORMATION Author notes * M M van den Heuvel-Eibrink and C Michel Zwaan: These authors contributed equally to this study. AUTHORS AND AFFILIATIONS * Department of Pediatric

Hematology/Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands J D E de Rooij, I H I M Hollink, S T C J M Arentsen-Peters, R Pieters, M M van den Heuvel-Eibrink &

 C Michel Zwaan * Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands J F van Galen & H Berna Beverloo * Department of Hematology, Hopital

Saint Louis, Paris, France A Baruchel * Department of Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic J Trka * AML-BFM Study Group, Pediatric

Hematology/Oncology, Medical School Hannover, Hannover, Germany D Reinhardt & M Zimmermann * Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands E Sonneveld * Department of

Biostatistics, University of Southern California, Los Angeles, CA, USA T A Alonzo * Fred Hutchinson Cancer Research Center, Seattle, WA, USA S Meshinchi Authors * J D E de Rooij View author

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CORRESPONDING AUTHOR Correspondence to C Michel Zwaan. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION AUTHOR CONTRIBUTIONS 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. Supplementary Information accompanies this paper on the Leukemia website SUPPLEMENTARY INFORMATION SUPPLEMENTARY

INFORMATION (DOC 1002 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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

Download citation * Received: 12 March 2013 * Accepted: 15 March 2013 * Published: 27 March 2013 * Issue Date: December 2013 * DOI: https://doi.org/10.1038/leu.2013.87 SHARE THIS ARTICLE

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by the Springer Nature SharedIt content-sharing initiative KEYWORDS * NUP98 * JARID1A * AML * HOX * cytogenetics * pediatric