AML-283 The Genetic Landscape of NUP98-Rearranged Pediatric Leukemia.

Clinical lymphoma, myeloma & leukemia 2022 Oct

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Rearrangements involving NUP98 are frequently found in pediatric acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL) and are associated with poor prognosis. Various fusion partners have been identified; however, the genetic basis of how different fusion genes and cooperating mutations contribute to the disease phenotypes and the refractory nature remains to be clarified. To elucidate the transcriptional and genetic background of pediatric NUP98-rearranged acute leukemia. Transcriptomic and genetic analyses were performed on pediatric leukemia with NUP98 rearrangements from multiple clinical studies at St. Jude Children's Research Hospital, by the Italian Association for Pediatric Hematology and Oncology, or by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. No blinding was done in this study. RNA sequencing from 95 patients (median age of 9.0 years) with NUP98-rearranged (NUP98r) leukemia was performed or obtained from previous studies. Eighty-one of these samples were also studied by tumor-normal-paired whole-genome or whole-exome sequencing. We identified 17 unique NUP98 fusion partners from RNAseq data with NSD1 as the most frequent partner (n=44, 46.3%), followed by KDM5A (n=27, 28.4%) and RAP1GDS1 (n=6, 6.3%). We also found rare fusion partners recurrent in this cohort, including LNP1, HOXA13, and HOXD13 (n=2, 2.1%, respectively). Among cooperating mutations, FLT3-ITD and WT1 were frequent in NSD1-AML (57.9% and 52.6%, respectively), and copy number loss of chromosome 13 harboring RB1 was found in 86.3% of NUP98-KDM5A AML with erythromegakaryocytic expression patterns (FAB M6-7). NUP98-RAP1GDS1 fusions are found in both AML (n=3) and T-ALL (n=3) cases and those with T lineage differentiation have concurrent NOTCH1 mutations, indicating that both fusions and cooperating mutations are contributing to the disease phenotypes. We further performed transcriptome analysis of NUP98r AML, integrating various AML subtypes from previous studies. NUP98r AML expressed high MEIS1, PRDM16, and HOXA-B cluster genes similar to AMLs with NPM1 or UBTF mutations, suggesting a molecular basis shared by these subtypes. Genomic and transcriptional profiling of pediatric NUP98-rearranged leukemia identified unique associations among fusions, cooperating mutations, and disease phenotypes. Copyright © 2022 Elsevier Inc. All rights reserved.

Citation

Masayuki Umeda, Nicole Michmerhuizen, Jing Ma, Tamara Westover, Michael P Walsh, Guangchun Song, Cristina Mecucci, Danika Di Giacomo, Franco Locatelli, Riccardo Masetti, Salvatore Nicola Bertuccio, Martina Pigazzi, Ilaria Iacobucci, Charles G Mullighan, Jeffery M Klco. AML-283 The Genetic Landscape of NUP98-Rearranged Pediatric Leukemia. Clinical lymphoma, myeloma & leukemia. 2022 Oct;22 Suppl 2:S233