Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Umeda M, Ma J, Huang BJ, Hagiwara K, Westover T, Abdelhamed S, Barajas JM, Thomas ME, Walsh MP, Song G, Tian L, Liu Y, Chen X, Kolekar P, Tran Q, Foy SG, Maciaszek JL, Kleist AB, Leonti AR, Ju B, Easton J, Wu H, Valentine V, Valentine MB, Liu YC, Ries RE, Smith JL, Parganas E, Iacobucci I, Hiltenbrand R, Miller J, Myers JR, Rampersaud E, Rahbarinia D, Rusch M, Wu G, Inaba H, Wang YC, Alonzo TA, Downing JR, Mullighan CG, Pounds S, Babu MM, Zhang J, Rubnitz JE, Meshinchi S, Ma X, Klco JM. Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia. Blood Cancer Discov. 2022 May 5;3(3):194-207. doi: 10.1158/2643-3230.BCD-21-0160. PubMed PMID: 35176137; PubMed Central PMCID: PMC9780084.

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.