TY - JOUR TI - Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia AU - Umeda, Masayuki AU - Ma, Jing AU - Huang, Benjamin J. AU - Hagiwara, Kohei AU - Westover, Tamara AU - Abdelhamed, Sherif AU - Barajas, Juan M. AU - Thomas, Melvin E. AU - Walsh, Michael P. AU - Song, Guangchun AU - Tian, Liqing AU - Liu, Yanling AU - Chen, Xiaolong AU - Kolekar, Pandurang AU - Tran, Quang AU - Foy, Scott G. AU - Maciaszek, Jamie L. AU - Kleist, Andrew B. AU - Leonti, Amanda R. AU - Ju, Bengsheng AU - Easton, John AU - Wu, Huiyun AU - Valentine, Virginia AU - Valentine, Marcus B. AU - Liu, Yen-Chun AU - Ries, Rhonda E. AU - Smith, Jenny L. AU - Parganas, Evan AU - Iacobucci, Ilaria AU - Hiltenbrand, Ryan AU - Miller, Jonathan AU - Myers, Jason R. AU - Rampersaud, Evadnie AU - Rahbarinia, Delaram AU - Rusch, Michael AU - Wu, Gang AU - Inaba, Hiroto AU - Wang, Yi-Cheng AU - Alonzo, Todd A. AU - Downing, James R. AU - Mullighan, Charles G. AU - Pounds, Stanley AU - Babu, M. Madan AU - Zhang, Jinghui AU - Rubnitz, Jeffrey E. AU - Meshinchi, Soheil AU - Ma, Xiaotu AU - Klco, Jeffery M. T2 - Blood Cancer Discovery AB - Abstract The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML. Significance: We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes. See related commentary by Hasserjian and Nardi, p. 173. This article is highlighted in the In This Issue feature, p. 171 DA - 2022/05/05/ PY - 2022 DO - 10.1158/2643-3230.BCD-21-0160 DP - DOI.org (Crossref) VL - 3 IS - 3 SP - 194 EP - 207 LA - en SN - 2643-3230, 2643-3249 UR - https://aacrjournals.org/bloodcancerdiscov/article/3/3/194/694690/Integrated-Genomic-Analysis-Identifies-UBTF-Tandem Y2 - 2022/08/26/22:15:13 ER -